Antimicrobial compounds, compositions, and articles of manufacture for selectively inhibiting pathogenic microbes

ABSTRACT

wherein ring A is a phenyl, indolyl, naphthyl, or benzothiazolyl; X is S, SO, or SO2; Y is a linker or bond; Z is CH, CR2, or N; Z1 is C or N to form an imidazopyridine; each Z2, Z3, or Z4 is independently CH, CR2, or N; each Z5 or Z6 is C or CH; each R1, R2, and R3 is independently a substituent, and at least one of R1, R2, or R3 is a substituent other than a hydrogen; m is 0, 1, 2, 3, or 4; and n is 0 or a positive integer. The compounds can have specific substituent patterns.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. Provisional ApplicationNo. 62/863,027 filed Jun. 18, 2019, which provisional is incorporatedherein by specific reference in its entirety.

GOVERNMENT RIGHTS

This invention was made with government support under W911NF-17-C-0076and W911NF-17-P-0075 awarded by the U.S. Army. The government hascertain rights in the invention.

BACKGROUND Field

The present disclosure relates to compounds for use as antimicrobials.In some aspects, the compounds may selectively inhibit pathogenicmicrobes over commensal microbes.

Description of Related Art

Many diseases, ranging from more minor ailments, such as upper and lowerrespiratory tract infections, to potentially fatal infections are due topathogenic microbes, including, for example, bacteria, viruses, andfungi. As a result, many compounds have been identified to be used intreatments against microbes. For example, chemical-based agents may beused for external treatment (e.g., on a hard surface) to preventcontamination and transmission to animals, and drugs may be used totreat an infected animal. While agents have been developed that aregenerally effective against various pathogens, there is increasingevidence that the use of such agents has certain limitations.Specifically, certain strains of pathogenic microbes have becomeincreasingly resistant to one or more antimicrobials, thereby renderingthe standard courses of treatment ineffective. Accordingly, higher dosesof antimicrobial treatments may be required to achieve efficacy, whichcan result in undesirable side effects and toxicity to both animals andthe environment.

Currently, the majority of antimicrobial compounds have been derivedfrom natural products. Traditional antimicrobial compounds are mostlybroad spectrum—inhibiting both pathogenic and commensal microbes.However, it may be beneficial to avoid inhibiting commensal microbeswhen inhibiting pathogenic microbes.

Therefore, it would be advantageous to have improved broad spectrumantimicrobial compounds, selective antimicrobial compounds thatpreferentially target pathogenic microbes, compositions, andcorresponding articles of manufacture that include the antimicrobialcompounds for use in methods of inhibiting microbial infections.

SUMMARY

In some embodiments, a method of selectively inhibiting pathogenicmicrobes can include: providing a compound that is functional as aselective antimicrobial having a structure of Formula 1, or derivativethereof, salt thereof, or stereoisomer thereof, or having any chiralityat any chiral center, or tautomer, polymorph, solvate, or combinationthereof; and contacting a pathogenic microbe with the compound such thatthe pathogenic microbe is selectively inhibited;

wherein: ring A is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, orpolycycle combination thereof; X is NH, O, CH₂, CH₂CH₂, N═N, S, SO, orSO₂; Y is a linker or bond; Z is CH, CR², or N; Z¹ is C or N to form animidazopyridine; each Z², Z³, or Z⁴ is independently CH, CR², or N; eachZ⁵ or Z⁶ is C or CH; each R¹, R², R³ and/or R⁴ is independently asubstituent; m is 0, 1, 2, 3, or 4; and n is zero or a positive integer.In some aspects, a composition can include the compound and a carrierhaving the compound. In some aspects, an article of manufacture caninclude: the compound and a material having the compound in a body ofthe material or in a surface of the material.

In some embodiments, a compound can have a structure of Formula A, orderivative thereof, salt thereof, or stereoisomer thereof, or having anychirality at any chiral center, or tautomer, polymorph, solvate, orcombination thereof:

wherein ring A is a phenyl, indolyl, naphthyl, or benzothiazolyl; X isNH, O, CH₂, CH₂CH₂, N═N, S, SO, or SO₂; Y is a linker or bond; Z is CH,CR², or N; Z¹ is C or N to form an imidazopyridine; each Z², Z³, or Z⁴is independently CH, CR², or N; each Z⁵ or Z⁶ is C or CH; each R¹, R²,and R³ is independently a substituent, and at least one of R¹, R², or R³is a substituent other than a hydrogen; m is 0, 1, 2, 3, or 4; and n is0 or a positive integer, and: when X is S and ring A is a phenyl, R¹ isa substituent other than a hydrogen; when X is S and ring A is abenzothiazolyl and linked to the Z⁵ carbon and R³ is hydrogen or alkyl,R² is not only a substituent on the Z³ carbon or only a hydrogen; when Xis S and ring A is phenyl and linked to the Z⁵ carbon and R² is only asubstituent on the Z³ carbon or hydrogen and R³ is hydrogen or alkyl, R¹is not a para-substituent when R¹ is a halogen, alkoxy, hydroxyl, oramine and R² is a halogen or alkoxy; when X is S and ring A is phenyland linked to the Z⁵ carbon and R² is only a halogen substituent on theZ³ carbon or a hydrogen, R¹ is not a ortho-substituent when R¹ is anamine or halogen and R² is a halogen or alkoxy; when X is S and ring Ais a naphthyl and linked to the Z⁵ carbon, R² is not only a substituenton the Z³ carbon or hydrogen, when X is S and ring A is phenyl andlinked to the Z⁵ carbon and R¹ is a para-substituent halogen, R³ is notan alkyl or

and when X is S and ring A is a phenyl and Z¹ is N and R² is hydrogenand R³ is hydrogen, R¹ is not a para-substituent halogen. In someaspects, a composition can include the compound and a carrier having thecompound. In some aspects, an article of manufacture can include thecompound and a material having the compound.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

The foregoing and following information as well as other features ofthis disclosure will become more fully apparent from the followingdescription and appended claims, taken in conjunction with theaccompanying drawings. Understanding that these drawings depict onlyseveral embodiments in accordance with the disclosure and are,therefore, not to be considered limiting of its scope, the disclosurewill be described with additional specificity and detail through use ofthe accompanying drawings.

FIG. 1A includes a graph that shows the cytotoxicity of an antimicrobialCompound 174I by membrane permeability versus factors of the MIC.

FIG. 1B includes a graph that shows the cytotoxicity of an antimicrobialCompound 156K by membrane permeability compared to the MIC or DMSO.

FIG. 1C shows an image with FM 4-64 stained B. subtilis cells imagedwith a fluorescence microscope.

FIG. 2A includes a graph that shows Compound 174I increasingly inhibitsglucosamine from incorporating into a cell wall of S. aureus strain withincreasing concentration.

FIG. 2B includes a graph that shows vancomycin increasingly inhibitsglucosamine from incorporating into a cell wall of S. aureus strain withincreasing concentration.

FIG. 2C includes a graph that shows the membrane permeability forCompound 174I and 174M by factors of MIC concentrations versus controls.

FIG. 3 includes a graph that shows the top upregulated genes by 174I and174M.

FIG. 4 shows examples of substituents for the compounds to include a PEGpolymer or a trimethoxy silane for use as a conjugation moiety.

FIGS. 5A-5B show that selective antimicrobials selectively inhibitpathogenic microbes over commensal microbes.

The elements and components in the figures can be arranged in accordancewith at least one of the embodiments described herein, and whicharrangement may be modified in accordance with the disclosure providedherein by one of ordinary skill in the art.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented herein. It will be readily understood that the aspects of thepresent disclosure, as generally described herein, and illustrated inthe figures, can be arranged, substituted, combined, separated, anddesigned in a wide variety of different configurations, all of which areexplicitly contemplated herein.

Generally, the present technology includes compounds for use asantimicrobials. In some aspects, the compounds can inhibit pathogenicmicrobes, such as bacteria, viruses, and fungi. The compounds can beused in methods for treating materials to be antimicrobial, and inmethods of treating subjects infected with a microbe. The compounds canbe prepared into various compositions, materials, or articles ofmanufacture for use as antimicrobials.

In some embodiments, the present technology includes compounds for useas selective antimicrobials. In some aspects, the compounds canselectively inhibit pathogenic microbes without significantly inhibitingcommensal microbes. As used herein, a commensal microbe is considered tobe any microbe that has commensalism, which is an association withanother organism (e.g., subject), such as a human or other animals(e.g., mammals, birds, etc.) where the microbe receives a benefit forthe association while the other organism may benefit and receives noharm from the association with the microbe. As used herein, a pathogenicmicrobe is considered to be any microbe that causes a disease state in asubject, such as a bacteria, virus, or fungus.

In some embodiments, the present invention relates to compounds that canbe used as selective antimicrobials that selectively inhibit pathogenicmicrobes more than inhibiting commensal microbes. That is, the compoundscan selectively inhibit pathogenic microbes in an amount or percent thatis greater than commensal microbes are inhibited. While the commensalmicrobes can be inhibited by the compounds, such inhibition issignificantly less than the inhibition of the pathogenic compounds.Thus, a greater degree of inhibition of the pathogenic microbes isachieved over inhibition of the commensal microbes.

In some embodiments, the selective antimicrobials can inhibitTrichophyton rubrum and Trichophyton mentagrophytes, which are thecausative agents of athlete's foot and jock itch. As such, thepathogenic microbes can include Burkholderia cenocepacia, Trichophytonrubrum and Trichophyton mentagrophytes. However, it should be recognizedthat the pathogenic microbes may include other skin-disease causingmicrobes. The compounds have been shown to be selective antimicrobialsagainst these pathologic microbes. It is thought that these compoundscan also be selective against other pathogenic microbes for theinhibition thereof. Thus, a variety of pathogenic microbes that arefungi, bacteria, or viruses can be selectively inhibited over commensalmicrobes.

In some embodiments, the commensal microbes can include Malasseziafurfur, Micrococcus sp., and Staphylococcus epidermidis. However, itshould be recognized that the commensal microbes may include othermicrobes, such as those that live on the skin (e.g., skin commensalmicrobes). The compounds have been shown to have limited inhibition oreffect on skin commensal microbes, such as those listed above. It isthought that these compounds can also be minimally active or havesignificantly reduced activity and inhibition against the skin commensalmicrobes, or other commensal microbes.

In some embodiments, the compounds described herein can be used asgeneral antimicrobials. In some embodiments, the antimicrobial compoundscan be used in any form and in any composition. The antimicrobialcompounds can be included in pharmaceutically acceptable carriers andadministered to a subject in need thereof. For example, the compoundscan be included in a topical composition for use against topicalpathogenic microbes, such as those that cause jock itch, athlete's foot,and others. The antimicrobial compounds can be included in variousliquids, gels, pastes, emulsions, or other non-solid formats.

In some embodiments, the antimicrobials can be applied to a solid,whether particulate, porous, non-porous, or in any non-liquid, non-gel,or non-flowable format. The solids can be those that may come intocontact with a skin of a subject, such as a human. The antimicrobialscan be applied to a surface of a solid object, and/or be embedded,encapsulated, or otherwise included within the solid body. Some examplesinclude fabrics, which may be used for various articles of manufacture,ranging from clothing (e.g., underwear, socks, pants, shorts, skirt,dress, shirt, blouse, jersey, hat, scarf, or other), bandages, tarps,floors, mats, carpets, towels, linens, furniture, mattress, cabinet,countertop, bathtub, sink, faucet, hot tub, toys, or the like, whetheras a coating (e.g., in a paint, caulk, or coating) or within thematerial thereof. The antimicrobials may be generally added to babyproducts or children products to protect them from the pathogenicmicrobes. The antimicrobials may be applied to athletic products thatare worn or used during a sport, such as to balls, bats, gloves, hats,uniforms, undergarments, shoes, or the like that come into contact withthe skin of a subject. The antimicrobial may be applied to campingproducts, such as those worn or used that come into contact with theskin of a subject, such as tents, sleeping bags, walking sticks, ropes,bungee cords, or the like. Any article of manufacture can include theantimicrobial compound. Some examples that have antimicrobials includefabrics, which may be used for various articles of manufacture, rangingfrom clothing (e.g., underwear, socks, pants, shorts, skirt, dress,shirt, blouse, jersey, hat, scarf, or other), footwear (e.g., shoes,sandals, flip flops, boat shoes), bandages, surgical drapes, tarps,floors, mats, carpets, towels, linens, furniture, mattress, cabinet,countertop, bathtub, sink, faucet, hot tub, toys, or the like, whetheras a coating (e.g., in a paint, caulk, or coating) or within thematerial thereof. Accordingly, the general antimicrobials can be appliedto any liquid carrier or any solid member (e.g., to surface or withinthe material).

The antimicrobials may be generally added to baby products or childrenproducts to protect them from the pathogenic microbes while allowing thecommensal microbes to be relatively unharmed (or significantly lessharm). The selective antimicrobial may be applied to athletic productsthat are worn or used during a sport, such as to balls, bats, gloves,hats, uniforms, undergarments, shoes, or the like that come into contactwith the skin of a subject. The selective antimicrobial may be appliedto camping products, such as those worn or used that come into contactwith the skin of a subject, such as tents, sleeping bags, walkingsticks, ropes, bungee cords, or the like. Any article of manufacture caninclude the selective antimicrobial compound. Some examples that haveselective antimicrobials include fabrics, which may be used for variousarticles of manufacture, ranging from clothing (e.g., underwear, socks,pants, shorts, skirt, dress, shirt, blouse, jersey, hat, scarf, orother), footwear (e.g., shoes, sandals, flip flops, boat shoes),bandages, surgical drapes, tarps, floors, mats, carpets, towels, linens,furniture, mattress, cabinet, countertop, bathtub, sink, faucet, hottub, toys, or the like, whether as a coating (e.g., in a paint, caulk,or coating) or within the material thereof. Accordingly, the selectiveantimicrobials can be applied to any liquid carrier or any solid member(e.g., to surface or within the material).

In some embodiments, the antimicrobials can be used to treat or inhibitan active microbial infection or microbial colony on an object or in aliquid. That is, any antimicrobial can be applied used against microbesthat are already present. However, the antimicrobials may also be usedin a prophylactic therapy to provide the antimicrobial prior to therebeing a microbial infection or colony. Here, the antimicrobial can beadministered to a person prior to being infected with the microbe in aprophylactic therapy. Also, the antimicrobial can be applied to objectsso that the antimicrobial is present and functional when or if theobject comes into contact with a microbe or otherwise inhibiting microbecolony formation on the object.

In some embodiments, the antimicrobials can be used as a treatment orprophylactic therapy for treating a biofilms or inhibiting or preventingformation of a biofilm. That is, the antimicrobial can be appliedbefore, during, or after formation of a biofilm. As used herein, a“biofilm” is at least one type of microbe growing in a colony or groupon a surface so as to form a film of the mirobe(s). Thus, theantimicrobials can inhibit formation or growth of biofilms.

In an aspect, the disclosure pertains to inhibitors of microbes, such asbacteria and fungi (antibacterials and antifungals) or viruses (e.g.,antivirals) derived from a specific compound; pharmaceuticalcompositions comprising disclosed compounds and their derivatives;methods of treating growth of bacteria and/or fungi and/or viruses in oron mammals and objects.

In some embodiments, the antimicrobial can include a structure underFormulae 1, 1A, 1B, 1C, or 1D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein:

In some embodiments, the structure of Formulae 1-ID can include ring Abeing any aromatic ring, polyaromatic, or ring structure having at leastone aromatic ring, any ring thereof with or without hetero atoms.Formula 1 can include any substituent R group for R¹, R², R³ and/or R⁴,such as those described herein or otherwise known. Each R group may beindependently selected, and each R¹, R², R³ and/or R⁴ on the same ringmay be independently selected from each other. As shown, “n” can be anyzero or integer depending on the structure of ring A. The “m” may be 0,1, 2, 3, or 4. X is NH, O, CH₂, CH₂CH₂, N═N, S, SO, or SO₂. The Y is abond (e.g., no atom for Y) or a linker. Each Z is independently CH or N.

In some embodiments, ring A is a cycloalkyl, heterocycloalkyl, aryl,heteroaryl, or polycycle combination thereof; X is NH, O, CH₂, CH₂CH₂,N═N, S, SO, or SO₂; Y is a linker or bond; Z is CH, CR², or N; Z¹ is Cor N to form an imidazopyridine; each Z², Z³, or Z⁴ is independently CH,CR², or N; each Z⁵ or Z⁶ is C or CH; each R¹, R², R³ and/or R⁴ isindependently a substituent; m is 0, 1, 2, 3, or 4; and n is zero or apositive integer. In some aspects, a composition can include thecompound and a carrier having the compound. In some aspects, an articleof manufacture can include: the compound and a material having thecompound in a body of the material or in a surface of the material.

In some embodiments of Formulae 1-ID, ring A is a cycloalkyl,heterocycloalkyl, aryl, heteroaryl, or polycycle combination thereof; Xis S, SO, or SO₂; Y is a linker or bond; Z is CH, CR², or N; Z¹ is C orN to form an imidazopyridine; each Z², Z³, or Z⁴ is independently CH,CR², or N; each Z⁵ or Z⁶ is C or CH; each R¹, R², R³ and/or R⁴ isindependently a substituent; m is 0, 1, 2, 3, or 4; and n is zero or apositive integer. In some aspects, ring A is an aromatic ring,polyaromatic, or ring structure having at least one aromatic ring, anyring thereof with or without hetero atoms.

In some embodiments, the compounds that can be general antimicrobialscan include derivatives of 4-(1H-indol-3-yl-sulfanyl) phenol, and somederivatives can be selective antimicrobials. In some aspects,4-(1H-indol-3-yl-sulfanyl) phenol and its close derivatives (e.g., paraR¹ hydroxyl substituent) are specifically omitted as a generalantimicrobial, or as a selective antimicrobial in some instances. Insome aspects, the omitted compounds have an R¹ hydroxyl in the paraposition. In some aspects, the omitted compounds have an R¹ hydroxyl inany position. In some aspects, the included compounds include a R², R³,or R⁴ substituent other than hydrogen with R¹ is a hydroxyl, such as thepara position.

In some embodiments, the antimicrobial can include a structure underFormulae 2, 2A, 2B, 2C, or 2D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein:

In Formulae 2, 2A, 2B, 2C, or 2D, or any other formula, each Q isindependently a CH, CR¹, N, or NH⁺. When NH⁺, there can be a counteranion so as to form a salt.

In some embodiments, the antimicrobial has a structure of Formula A2,A2A, A2B, A2C, or A2D, or derivative, salt thereof, or stereoisomerthereof, or having any chirality at any chiral center, or tautomer,polymorph, solvate, or combination thereof;

In the Formula A2-A2D, Q is independently a CH, CR¹, N, or NH⁺.

In some embodiments, the antimicrobial has a structure of Formula B2,B2A, B2B, B2C, or B2D, or derivative, salt thereof, or stereoisomerthereof, or having any chirality at any chiral center, or tautomer,polymorph, solvate, or combination thereof;

In some embodiments, the antimicrobial has a structure of Formula C2,C2A, C2B, C2C, or C2D, or derivative, salt thereof, or stereoisomerthereof, or having any chirality at any chiral center, or tautomer,polymorph, solvate, or combination thereof;

In the different Formulae, each R^(1A), R^(1B), R^(1C), R^(1D), and/orR^(1E) is independently a substituent; and each R^(2A), R^(2B), R^(2C),and/or R^(2D) is independently a substituent. In some aspects, In thedifferent Formulae, each R^(1A), R^(1B), R^(1C), R^(1D), and/or R^(1E)is independently a substituent as defined for R¹. In some aspects, eachR^(2A), R^(2B), R^(2C), and/or R^(2D) is independently a substituent asdefined for R². In some aspects, R³ is as defined herein. In someaspects, R⁴ is as defined herein.

In some embodiments, Formula C2D includes: R^(1A) being F, CF₃, CH₃,carboxy (e.g., carboxylic acid C(O)OH), or methanol; R^(1C) being H orF; R^(2B) being Br, CH₃, or CF₃; R³ being methyl, ethyl, isopropyl, ortert-butyl; R⁴ is H; the rest of the R groups are H; and X is NH, O,CH₂, CH₂CH₂, N═N, S, SO, or SO₂.

In some embodiments, the antimicrobial can include a structure underFormula 3, 3A, 3B, 3C, or 3D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein:

In some embodiments, the antimicrobial can include a structure underFormula A3, A3A, A3B, A3C, or A3D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein:

In some embodiments, the antimicrobial can include a structure underFormula 4, 4A, 4B, 4C, or 4D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein.

In the Formulae 4-4D, X¹ is CH or N; and X² is CH, CH₂ or S.

In some embodiments, the antimicrobial can include a structure underFormula A4, A4A, A4B, A4C, or A4D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein.

In some embodiments, the antimicrobial has a structure of Formula B4,B4A, B4B, B4C, or B4D, or derivative, salt thereof, or stereoisomerthereof, or having any chirality at any chiral center, or tautomer,polymorph, solvate, or combination thereof, as presented herein.

In the formulae, each R^(1A), R^(1B), R^(1C), and/or R^(1D) isindependently a substituent; and each R^(2A), R^(2B), R^(2C), and/orR^(2D) is independently a substituent.

In some embodiments, each R^(1A), R^(1B), R^(1C), R^(1D) and/or R^(1E)is independently as defined for R¹.

In some embodiments, each R^(2A), R^(2B), R^(2C), and/or R^(2D) isindependently as defined for R².

In some embodiments, R³ can be a hydrogen, C₁-C₆ alkyl, or a substitutedC₁-C₆ alkylamine. In some embodiments, R³ can be a hydrogen, C₁-C₅alkyl, or a substituted C₁-C₅ alkylamine. In some embodiments, R³ can bea hydrogen, C₁-C₄ alkyl, or a substituted C₁-C₄ alkylamine. In someembodiments, R³ can be a hydrogen, C₁-C₃ alkyl, or a substituted C₁-C₃alkylamine.

In some embodiments, the antimicrobial can include a structure underFormula 5, 5A, 5B, 5C, or 5D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein.

In some embodiments, the antimicrobial can include a structure underFormula 6, 6A, 6B, 6C, or 6D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein.

In some embodiments, the antimicrobial can include a structure underFormula 7, 7A, 7B, 7C, or 7D, or derivative, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof, as presentedherein.

In some embodiments, Y is a linker or a bond between the X atom and thering A, or the ring structure shown in the formulae, the linker can havea linker chain having one or more chain atoms. In some embodiments, Y isa bond (e.g., sometimes considered “nothing” as there is no atom for Y).Accordingly, each Y can be removed from each formulae herein when Y is abond or Y does not include any atoms. When Y is one chain atom or morethan one chain atom, there may be a R substituent on one or more of thechain atoms. The linker can be a hydrocarbon chain with or without oneor more hetero atoms, such as O, N, or S. The linker may includestraight aliphatics, branched aliphatics, cyclic aliphatics, substitutedaliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturatedaliphatics, aromatics, polyaromatics, substituted aromatics,hetero-aromatics, amines, primary amines, secondary amines, tertiaryamines, aliphatic amines, carbonyls, carboxyls, amides, esters, aminoacids, peptides, polypeptides, derivatives thereof, substituted orunsubstituted, or combinations. In some aspects, the linker can includeC₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₆-C₂₀ aryl, C₇-C₂₄alkaryl, C₇-C₂₄ aralkyl, amino, mono- and di-(alkyl)-substituted amino,mono- and di-(aryl)-substituted amino, alkylamido, arylamido, imino,alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,phosphono, phosphonato, phosphinato, phospho, phosphino, any with orwithout hetero atoms, derivatives thereof, and combinations thereof. Insome aspects, the linker can include C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, any with or without hetero atoms, derivatives thereof,and combinations thereof. In some aspects, the linker can include C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, any with or without hetero atoms,derivatives thereof, and combinations thereof. In some aspects, thelinker can include C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, any withor without hetero atoms, derivatives thereof, and combinations thereof.In some aspects, the linker can include C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, any with or without hetero atoms, derivatives thereof,and combinations thereof. In some aspects, the linker can include C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, any with or without hetero atoms,derivatives thereof, and combinations thereof. In some aspects, thelinker can include C₁-C₃ alkyl any with or without hetero atoms,derivatives thereof, and combinations thereof. In some aspects, thelinker can include C₁-C₂ alkyl any with or without hetero atoms,derivatives thereof, and combinations thereof.

In the formulae, ring A can be any ring structure with a single ring ortwo or more fused rings, which can be cycloaliphatic, heterocycloaliphatic, aryl, hetero aryl, polyaryl, poly hetero aryl,polycycloalkylaryl, or combinations thereof with 4, 5, 6, 7, 8, 9, 10,11, or more 12 atoms. When including hetero atoms, they can be C, O, N,S, or P and depend on the number of bonds therewith, and any ring A caninclude 1, 2, 3, 4, 5, 6 or more hetero atoms. Ring A can be substitutedwith one or more R¹ groups. The number of R¹ group substituents for ringA are determined by the number of atoms in the ring when single ringsbeing n−1 (not fused rings) where n is the number of ring atoms. Each Rgroup substituent on a ring can be different from the others.

In the formulae, the Q and/or Z ring atoms can be carbon (C) or a heteroatom, such as O, N, S, P or other with appropriate hydrogens or R groupsubstituents. As noted, when carbon, the Q and/or Z ring atom may or maynot have a substituent, which can be on any atom of the respective ring,such as on the Q and/or Z ring atom.

In some embodiments, X² can be a C (e.g., CH₂) or O or N (e.g., NH) or Sor P (e.g., PH), with the appropriate hydrogen atoms. The X¹ can be a C(e.g., CH) or N or P, with the appropriate hydrogen atoms.

In the formulae, the R substituent groups, such as R¹, R², R³, and R⁴can be any possible substituent or one substituent or a combination ofthe substituents recited herein. Depending on the ring atom ofconjugation, there may or may not be an R substituent group. These Rsubstituent groups can be on one or more ring atoms or linker atom(e.g., Y). As such, each atom of a ring or linker atom may include asubstituent as shown in Formula A. Each R substituent for a specificatom can be any possible substituent or one substituent or a combinationof substituents.

In some embodiments, each R¹, R², R³ and/or R⁴ is independentlyhydrogen, halogens, hydroxyls, alkoxys, straight aliphatics, branchedaliphatics, cyclic aliphatics, substituted aliphatics, unsubstitutedaliphatics, saturated aliphatics, unsaturated aliphatics, aromatics,polyaromatics, substituted aromatics, hetero-aromatics, amines, primaryamines, secondary amines, tertiary amines, aliphatic amines, carbonyls,carboxyls, amides, esters, amino acids, peptides, polypeptides,polymers, conjugation moieties, derivatives thereof, substituted orunsubstituted, or combinations thereof as well as other well-knownchemical substituents, and combinations thereof. When on a hetero atom,the R¹, R², R³, or R⁴ may be devoid of a substituent, and therebynothing but electrons, such as electron pairs etc.

In some embodiments, each R¹, R², R³ and/or R⁴ is independentlyhydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, halo,hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, acyl,alkylcarbonyl, arylcarbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl,ether, halocarbonyl, alkylcarbonato, arylcarbonato, carboxy,carboxylato, carbamoyl, mono-(alkyl)-substituted carbamoyl,di-(alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl,thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato,isothiocyanato, azido, formyl, thioformyl, amino, mono- anddi-(alkyl)-substituted amino, mono- and di-(aryl)-substituted amino,alkylamido, arylamido, imino, alkylimino, arylimino, nitro, nitroso,sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl,arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphine, polymers, conjugation moieties, anywith or without hetero atoms, any including straight chains, anyincluding branches, and any including rings, derivatives thereof, andcombinations thereof.

In some embodiments, each R¹, R², R³ and/or R⁴ is independently any oneor more of the substituents selected from the group of hydrogen, C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl,C₆-C₂₄ aralkyl, C₁-C₂₄ polyether (e.g., PEG), halo, hydroxyl,sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl(—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), halogenatedC₁-C₂₄ alkyls, halocarbonyl (—CO)—X where X is halo), C₂-C₂₄alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),mono-(C₁-C₂₄ alkyl)-substituted carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)),di-(C₁-C₂₄ alkyl)-substituted carbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂),mono-substituted arylcarbamoyl (—(CO)—NH-aryl), di-substitutedarylcarbamoyl (—(CO)—NH-aryl)₂, thiocarbamoyl (—(CS)—NH₂), mono-(C₁-C₂₄alkyl)-substituted thiocarbamoyl (—(CS)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl (—(CS)—N(C₁-C₂₄ alkyl)₂),mono-substituted arylthiocarbamoyl (—(CS)—NH-aryl), di-substitutedarylthiocarbamoyl (—(CS)—NH-aryl)₂, carbamido (—NH—(CO)—NH₂),),mono-(C₁-C₂₄ alkyl)-substituted carbamido (—NH—(CO)—NH(C₁-C₂₄ alkyl)),di-(C₁-C₂₄ alkyl)-substituted carbamido (—NH—(CO)—N(C₁-C₂₄ alkyl)₂),mono-substituted aryl carbamido (—NH—(CO)—NH-aryl), di-substituted arylcarbamido (—NH—(CO)—N-(aryl)₂) cyano(—C≡N), isocyano (—N⁺≡C⁻), cyanato(—O—C≡N), isocyanato (—O—N⁺≡C⁻), thiocyanato (—S—C≡N), isothiocyanato(—S—N⁺≡C⁻), azido (—N═N⁺═N⁻), formyl (—(CO)—H), thioformyl (—(CS)—H),amino (—NH₂), mono- and di-(C₁-C₂₄ alkyl)-substituted amino, mono- anddi-(C₆-C₂₀ aryl)-substituted amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl),C₅-C₂₀ arylamido (—NH—(CO)-aryl), imino (—CR═NH where R is hydrogen,C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.),alkylimino (—CR═N(alkyl), where R=hydrogen, C₁-C₂₄ alkyl, aryl, alkaryl,aralkyl, etc.), arylimino (—CR═N(aryl), where R=hydrogen, alkyl, aryl,alkaryl, etc.), nitro (—NO₂), nitroso (—NO), sulfonic acid (—SO₂—OH),sulfonato (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed“alkylthio”), C₅-C₂₀ arylsulfanyl (—S-aryl; also termed “arylthio”),C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl (—(SO)-aryl),C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl (—SO₂-aryl),phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato(—P(O)(O—)), phospho (—PO₂), phosphine (—PH₂), diazirine (N═N), alkyldiazirine, polymers, conjugation moieties, any with or without heteroatoms (e.g., N, O, P, S, or other) where the hetero atoms can besubstituted (e.g., hetero atom substituted for carbon in chain or ring)for the carbons or in addition thereto (e.g., hetero atom added tocarbon chain or ring) swapped, any including straight chains, anyincluding branches, and any inducing rings, derivatives thereof, andcombinations thereof.

In some embodiments, each R¹, R², R³ and/or R⁴ is independently asubstituent as described herein that further includes an end group thatis functional as a conjugation moiety. That is, any substituent recitedherein can further include a conjugation moiety at a terminal end, whichconjugation moiety can be used to link the antimicrobial to a substrateor any material. The examples of conjugation moieties can include alkoxysilanes (e.g., triethoxy silane), biotin, carboxylic acid, amine,halide, or any other common reactive chemical moiety that can be used toform a covalent bond with a substrate. In some aspects, only R² or R³may be a substituent as described herein that further includes an endgroup that is functional to function as a conjugation moiety. In someaspects, R⁴ is hydrogen.

In some embodiments, each R¹, R², R³ and/or R⁴ is independently asubstituent as described herein that further includes a polymer, such asa water soluble polymer, such as a poly ether (e.g., PEG). The polymercan be attached to the ring structure, within the substituent, or as aterminal portion of the substituent. For example, the antimicrobials canbe PEGylated for improved water solubility. In some aspects, only R² orR³ may be a substituent as described herein that further includes apolymer. In some aspects, R⁴ is hydrogen.

In some embodiments, ring A includes: at least one phenyl group,pyrimidyl group, triazinyl group, or pyridyl group; a thiazole fused toa phenyl group, pyrimidyl group, triazinyl group, or pyridyl group;indolyl group; naphthyl group; a benzothiazole group; thiadiazol group;thiazole group; or at least two fused rings including a phenyl group,pyrimidyl group, triazinyl group, and/or pyridyl group.

In some embodiments, Y is a bond or an aliphatic linker.

In some embodiments, each R¹, R², R³ and/or R⁴ is independently H, F,Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e., CH3C═O), propionyl,butyryl, acetamide (i.e., acetylamino), propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl(i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl.

In some embodiments, each R¹ is independently H, hydroxyl, Br, Cl, F,carboxyl, alkyl ester, alkyoxy, or combination thereof; each R² isindependently H, OH, Br, Cl, F, carboxyl, alkyl ester, alkyoxy, nitrogendioxide, or combination thereof; R³ is independently H, alkyl, alkylester, or combinations thereof or R³ is

and R⁴ is independently H or alkyl.

In some embodiments, each R¹ is independently H, hydroxyl, halogen(e.g., Br, Cl, F), carboxyl, alkyl ester, alkyoxy, amino, nitro,halogenated alkyl (e.g., CF₃), or combination thereof.

In some embodiments, each R¹ is independently H, OH, Br, Cl, F, —COOH,—COOCH₃, —OCH₃, halogenated alkyl (e.g., CF₃), amino, nitro, orcombination thereof.

In some embodiments, each R² is independently H, OH, Br, Cl, F,carboxyl, alkyl ester, alkyoxy, halogenated alkyl (e.g., CF₃), amino,nitro, or combination thereof.

In some embodiments, each R² is independently H, OH, Br, Cl, F, —COOH,—COOCH₃, —OCH₃, NO₂, halogenated alkyl (e.g., CF₃), amino, nitro, orcombination thereof.

In some embodiments, R³ is independently H, alkyl, alkyl ester,halogenated alkyl, or combinations thereof.

In some embodiments, R³ is independently H, methyl, ethyl, propyl,butyl, —COOCH₃, CF₃, or combination thereof.

In some embodiments, R⁴ is independently H or alkyl.

In some embodiments, R⁴ is independently H, methyl, ethyl, propyl, orbutyl.

In some embodiments, X is NH, O, CH₂, CH₂CH₂, N═N, S, SO, or SO₂.

In some embodiments, X is a variable other than S.

In some embodiments, at least one Q is a NH⁺, and the compound is asalt.

In some embodiments, wherein the salt includes a negative counter ionassociated with the Q when a NH⁺.

In some embodiments, wherein the salt includes a CH₃COO⁻.

In some embodiments, wherein each R¹, R², R³ and/or R⁴ is independentlyselected from hydrogen, halogen, cyano, hydroxyl, —NO₂, —NH₂, —SF₅,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₁-C₆ haloalkyl, and C₁-C⁶hydroxyalkyl, or combination thereof.

In some embodiments, each R¹, R², R³ and/or R⁴ independently can includea diazirine group, such as an alkyl diazirine. An example is3-isopropyl-3-methyl-3H-diazirine.

In some embodiments, R² or R³ includes a terminal alkoxy silane group.The alkoxy silane can be a di-alkoxy silane or tri-alkoxy silane. Forexample, the alkoxy silane can be triethoxy silane. An example of thetriethoxy silane-containing substituent is provided as

In some embodiments, the antimicrobials can include (showing theCompound Number, e.g., 156I, referenced to the table below):

Compound Compound structure ID

156I

156K

156O

156P

172A

172B

172C

172D

172E

172G

172I

172J

174A

174AA

174AB

174AC

174AD

174AE

174AF

174AG

174AH

174AI

174AJ

174AK

174AL

174AN

174AO

174AP

174AQ

174AR

174AS

174AT

174AU

174AV

174AX

174AY

174AZ

174C

174D

174E

174G

174H

174I

174J

174K

174L

174M

174N

174O

174P

174Q

174R

174S

174T

174U

174V

174W

174X

174Y

174Z

177A

177B

177C

177D

177E

177F

177G

177H

177I

156L

156M

156N

172F

174B

172H

156SI

174SI

In some embodiments, the antimicrobial methods include using a compoundthat is selected from the group of (structure name (Compound No.)):3-((4-bromophenyl)thio)-6-fluoro-1H-indole (172A);2-((4-bromophenyl)thio)-3-methyl-1H-indole (172B); methyl3-((4-bromophenyl)thio)-1H-indole-5-carboxylate (172G);5-bromo-3-((4-bromophenyl)sulfinyl)-1H-indole (172I);5-bromo-3-((4-bromophenyl)sulfonyl)-1H-indole (172J);6-bromo-3-((4-bromophenyl)thio)-1H-indole (174A);5,6-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AB);5,7-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AC);5-bromo-3-((perchlorophenyl)thio)-1H-indole (174AD);4,6-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AE);5-bromo-3-((4-bromophenyl)thio)-6-chloro-1H-indole (174AF);5-bromo-3-((2,4,6-trichlorophenyl)thio)-1H-indole (174AG);5-bromo-3-((3,4,5-tribromophenyl)thio)-1H-indole (174AH);2-((5-bromo-1H-indol-3-yl)thio)phenol (174AI);5-bromo-3-((2-chlorophenyl)thio)-1H-indole (174AJ);3-((2-aminophenyl)thio)-2-methyl-1H-indol-5-ol (174AK);3-((1H-indol-3-yl)thio)-5-bromo-1H-indole (174AL);3-((4-bromophenyl)thio)imidazo[1,2-a]pyridine (174AN);3-((2-hydroxyphenyl)thio)-2-methyl-1H-indol-5-ol (174AO);3-((2-hydroxyphenyl)thio)-1H-indol-5-ol (174AP);2-((5-methoxy-1H-indol-3-yl)thio)phenol (174AQ);3-((2-bromophenyl)thio)-1H-indol-5-ol (174AR);3-((2-bromophenyl)thio)-5-methoxy-1H-indole (174AS);(2-((5-bromo-1H-indol-3-yl)thio)phenyl)methanol (174AT);5-bromo-3-((2-fluorophenyl)thio)-1H-indole (174AU);5-bromo-3-((2-(trifluoromethyl)phenyl)thio)-1H-indole (174AV);3-((2-bromophenyl)thio)-5-(trifluoromethyl)-1H-indole (174AX);5-bromo-3-(o-tolylthio)-1H-indole (174AY);5-bromo-3-((2-bromophenyl)thio)-2-methyl-1H-indole (174AZ);4-bromo-3-((4-bromophenyl)thio)-1H-indole (174D);3-((4-bromophenyl)thio)-5-fluoro-1H-indole (174E);5-bromo-3-(naphthalen-1-ylthio)-1H-indole (174G);7-bromo-3-((4-bromophenyl)thio)-1H-indole (174H);5-bromo-3-((3-bromophenyl)thio)-1H-indole (174N);5-bromo-3-((4-bromobenzyl)thio)-1H-indole (174O);3-([1,1′-biphenyl]-4-ylthio)-5-bromo-1H-indole (174R);5-bromo-3-((2,3-dichlorophenyl)thio)-1H-indole (174T);5-bromo-3-((2,4-dichlorophenyl)thio)-1H-indole (174V);5-bromo-3-((3,4-dichlorophenyl)thio)-1H-indole (174W);5-bromo-2-((5-bromo-1H-indol-3-yl)thio)aniline (174X);3-((5-bromo-1H-indol-3-yl)thio)aniline (174Y);2-((5-(trifluoromethyl)-1H-indol-3-yl)thio)phenol (177A);4-((5-(trifluoromethyl)-1H-indol-3-yl)thio)phenol (177B);2-((5-(trifluoromethyl)-1H-indol-3-yl)thio)aniline (177C);3-((2-fluorophenyl)thio)-5-(trifluoromethyl)-1H-indole (177D);3-((2-bromophenyl)thio)-5-fluoro-1H-indole (177E);5-(trifluoromethyl)-3-((2-(trifluoromethyl)phenyl)thio)-1H-indole(177F); 3-((2-ethylphenyl)thio)-5-(trifluoromethyl)-1H-indole (177G);(5-bromo-3-((2-bromophenyl)thio)-1H-indol-2-yl)methanol (177H);(3-((2-ethylphenyl)thio)-5-(trifluoromethyl)-1H-indol-2-yl)methanol(177I); 4-((1H-indol-3-yl)thio)phenol (156I);3-((4-bromophenyl)thio)-1H-indole (156K);3-((4-methoxyphenyl)thio)-1H-indole (1560);2,3-bis((4-bromophenyl)thio)-1H-indole (156P);3-((4-bromophenyl)thio)-2-methyl-1H-indole (172C);5-bromo-3-((4-bromophenyl)thio)-1H-indole (172D);3-((4-bromophenyl)thio)-5-methoxy-1H-indole (172E);5-bromo-3-(phenylthio)-1H-indole (174AA);3-((4-bromophenyl)thio)-5-chloro-1H-indole (174C);5-bromo-3-((2-bromophenyl)thio)-1H-indole (174I);5-bromo-3-((4-chlorophenyl)thio)-1H-indole (174J);3-(benzylthio)-5-bromo-1H-indole (174K);2-((5-bromo-1H-indol-3-yl)thio)benzo[d]thiazole (174L);2-((5-bromo-1H-indol-3-yl)thio)aniline (174M);5-bromo-3-((4-fluorophenyl)thio)-1H-indole (174P);5-bromo-3-((4-methoxyphenyl)thio)-1H-indole (174Q);5-bromo-3-(naphthalen-2-ylthio)-1H-indole (174S);3-((4-bromophenyl)thio)-1H-indole (174U);4-((5-bromo-1H-indol-3-yl)thio)aniline (174Z); 3-(phenylthio)-1H-indole(156L); 3-(pyridin-2-ylthio)-1H-indole (156M);2-((1H-indol-3-yl)thio)benzoic acid (156N);3-((4-bromophenyl)thio)-1H-pyrrolo[2,3-b]pyridine (172F); ethyl3-((4-bromophenyl)thio)-1H-indole-2-carboxylate (172H); and/or3-((4-bromophenyl)thio)-1-methyl-1H-indole (174B);N-((3-((4-hydroxyphenyl)thio)-1H-indol-5-yl)methyl)-4-(triethoxysilyl)butanamide(156SI); and/or3-((2-aminophenyl)thio)-5-bromo-N-(3-(triethoxysilyl)propyl)-1H-indole-2-carboxamide(174SI).

In some embodiments, the antimicrobial methods can include contacting apathogenic microbe with the compound such that the pathogenic microbe isselectively inhibited over a commensal microbe that contacts thecompound. In some aspects, the method can include administering theselective antimicrobial compound to a subject.

In some embodiments, the methods can include applying the compound to asurface or within a body of an object. In some aspect, the objectincludes fabrics, bandages, tarps, flooring, mats, carpets, towels,linens, furniture, mattress, cabinet, countertop, bath tub, sink,faucet, hot tub, toys, underwear, socks, pants, shorts, skirt, dress,shirt, blouse, jersey, hat, scarf, medical devices, medical dressings,medical clothing, bed linens, privacy curtains, toys, bottles, crib,athletic equipment, handles, grips, camping items, pharmaceutical dosageform, or combinations thereof.

In some embodiments, the pathogenic microbe is a bacterium, virus, or afungus. As such, the antimicrobial compound can be antibacterial,antiviral, or antifungal.

In some embodiments, the method can include contacting a pathogenicmicrobe with the compound such that the pathogenic microbe isselectively inhibited over a commensal microbe that contacts thecompound.

In some embodiments, the method can include administering the compoundto a subject.

In some embodiments, the method can include applying the compound to theskin of a subject.

In some embodiments, the method can include applying the compound to theskin of a subject at or around a groin area and/or feet area.

In some embodiments, the method can include applying the compound to asurface of an object.

In some embodiments, the subject has a pathogenic microbe infection.

In some embodiments, the method can include diagnosing the subject tohave the pathogenic microbe infection.

In some embodiments, the pathogenic microbe is a bacterium or a fungus.

In some embodiments, the selective antimicrobial is applied to a solidobject, whether particulate, porous, non-porous.

In some embodiments, the solid object is contacted to the skin of thesubject.

In some embodiments, the method includes applying the selectiveantimicrobial to a surface of an object.

In some embodiments, the object includes fabrics, bandages, tarps,flooring, mats, carpets, towels, linens, furniture, mattress, cabinet,countertop, bathtub, sink, faucet, hot tub, toys, or combinationsthereof.

In some embodiments, the object includes underwear, socks, pants,shorts, skirt, dress, shirt, blouse, jersey, hat, scarf, or combinationsthereof.

In some embodiments, object includes children or baby items.

In some embodiments, the object includes athletic equipment.

In some embodiments, the object includes camping items.

In some embodiments, the invention is a compound of one of theembodiments.

In some embodiments, the invention is a composition having the compoundof one of the embodiments.

In some embodiments, the invention is an object or article ofmanufacture having the compound of one of the embodiments.

In some embodiments, the object or pharmaceutical composition caninclude any of the compounds described herein that can be antimicrobial.

In some embodiments, the methods can include any of the compoundsdescribed herein that can be antimicrobial.

In one embodiment, a pharmaceutical composition can include a compoundof one of the embodiments, and a pharmaceutically acceptable carriercontaining the compound. In one aspect, the compound is present in atherapeutically effective amount to treat or inhibit a disease state. Inone aspect, the disease state is a microbial infection.

Pharmaceutical compositions can include the compounds of the invention,and can include, without limitation, lyophilized powders or aqueous ornon-aqueous sterile injectable solutions or suspensions, which mayfurther contain antioxidants, buffers, bacteriostats and solutes thatrender the compositions substantially compatible with the tissues or theblood of an intended recipient. Other components that may be present insuch compositions include water, surfactants (e.g., Tween®), alcohols,polyols, glycerin and vegetable oils, for example. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, tablets, or concentrated solutions or suspensions.The composition may be supplied, for example but not by way oflimitation, as a lyophilized powder which is reconstituted with sterilewater or saline prior to administration to the patient.

Suitable pharmaceutically acceptable carriers include essentiallychemically inert and nontoxic compositions that do not interfere withthe effectiveness of the biological activity of the pharmaceuticalcomposition. Examples of suitable pharmaceutical carriers include, butare not limited to, water, saline solutions, glycerol solutions,ethanol, N-(l (2,3-dioleyloxy)propyl)N,N,N-trimethylammonium chloride(DOTMA), diolesyl-phosphotidyl-ethanolamine (DOPE), and liposomes. Suchcompositions should contain a therapeutically effective amount of thecompound, together with a suitable amount of carrier so as to providethe form for direct administration to the patient.

The compositions described herein can be administered for example, byparenteral, intravenous, subcutaneous, intramuscular, intracranial,intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal,intracistemal, intraperitoneal, intranasal, aerosol or oraladministration. Common carriers or excipients can be used for preparingpharmaceutical compositions designed for such routes of administration.

In some embodiments, the methods omit use of Compound 156I(4-((1H-indol-3-yl)thio)phenol) in any methods or in any composition orin any article of manufacture. Accordingly, the compounds used in theinvention may omit a hydroxyl as a para-substituent on the ring A of thecompound. In some aspects, the compounds may omit a hydroxyl as apara-substituent on the ring A of the compound when there is no R²substituent. In some aspects, the compounds may omit a hydroxyl as apara-substituent on the ring A of the compound when there is no R³substituent. In some aspects, the compounds may omit a hydroxyl as apara-substituent on the ring A as the only R¹ substituent of thecompound. In some aspects, the compounds may omit a hydroxyl as apara-substituent on the ring A, unless there is another R¹ substituent,a R² substituent, or a R³ substituent. In some aspects, the compoundsmay omit a hydroxyl as a para-substituent on the ring A when linked tothe Z⁵ carbon. In some aspects, the compounds may omit a hydroxyl as asubstituent on the ring A.

In some embodiments, the compounds may omit a para-substituent on thering A when there is no other R¹ substituent. In some aspects, thecompounds may omit a para-substituent on the ring A when there is a R²substituent on the Z³ carbon. In some aspects, the compounds may omit apara-substituent on the ring A. In some aspects, the compounds may omita para-substituent on the ring A when there is only a R² substituent onthe Z³ carbon.

In some embodiments, the methods omit using the antimicrobial compoundsto inhibit B. subtilis, S. aurens, S. viridochromogenes, E. coli, C.alicans, and/or M. miehei. In some aspects, the methods omit usingCompound 156I or other compound having a hydroxy as a R¹para-substituent on ring A. In some aspects, the methods omit using anycompound recited herein as omitted.

In some embodiments, a method is provided to inhibit a microbe bycontacting the compound to the microbe. The contacting may includehaving the compound on a surface of an object, such as an article ofmanufacture.

In some embodiments, the microbe is only a bacterium. In someembodiments, the microbe is only a fungus. In some embodiments, themicrobe is only a virus. In these embodiments, the microbes areinhibited by the compounds. In these embodiments, the microbes arepathogenic microbes that are inhibited. In these embodiments, thepathogenic microbes are inhibited more than commensal microbes.

In some embodiments, the microbes that are inhibited are recited in thetables herein.

Compounds

In some embodiments, the present invention includes select compounds,which can be used as antimicrobials as recited herein. In theseembodiments, the present invention includes the compounds andcompositions thereof. These compounds and compositions can be used inthe methods recited herein. The compounds that are provided herein arerecited to be inventive compounds. While all of the compounds can beused in the methods, the compounds recited in this section are novel andcan be provided as compounds or in compositions for use in the recitedmethods or in other methods.

In some embodiments, a compound can have a structure of Formula A, orderivative thereof, salt thereof, or stereoisomer thereof, or having anychirality at any chiral center, or tautomer, polymorph, solvate, orcombination thereof:

The variables of the compounds of the formulae can include thefollowing: ring A is a phenyl, indolyl, naphthyl, or benzothiazolyl; Xis NH, O, CH₂, CH₂CH₂, N═N, S, SO, or SO₂; Y is a linker or bond; Z isCH, CR², or N; Z¹ is C or N to form an imidazopyridine; each Z², Z³, orZ⁴ is independently CH, CR², or N; each Z⁵ or Z⁶ is C or CH; each R¹,R², and R³ is independently a substituent, and at least one of R¹, R²,or R³ is a substituent other than a hydrogen; m is 0, 1, 2, 3, or 4; andn is 0 or a positive integer. In some aspects, the following criteriaapply to the compounds: when X is S and ring A is a phenyl, R¹ is asubstituent other than a hydrogen; when X is S and ring A is abenzothiazolyl and linked to the Z⁵ carbon and R³ is hydrogen or alkyl,R² is not only a substituent on the Z³ carbon or only a hydrogen; when Xis S and ring A is phenyl and linked to the Z⁵ carbon and R² is only asubstituent on the Z³ carbon or hydrogen and R³ is hydrogen or alkyl, R¹is not a para-substituent when R¹ is a halogen, alkoxy, hydroxyl, oramine and R² is a halogen or alkoxy; when X is S and ring A is phenyland linked to the Z⁵ carbon and R² is only a halogen substituent on theZ³ carbon or a hydrogen, R¹ is not a ortho-substituent when R¹ is anamine or halogen and R² is a halogen or alkoxy; when X is S and ring Ais a naphthyl and linked to the Z⁵ carbon, R² is not only a substituenton the Z³ carbon or hydrogen, when X is S and ring A is phenyl andlinked to the Z⁵ carbon and R¹ is a para-substituent halogen, R³ is notan alkyl or

and when X is S and ring A is a phenyl and Z¹ is N and R² is hydrogenand R³ is hydrogen, R¹ is not a para-substituent halogen.

In some embodiments, the variables of the formulae of this section canbe the same as defined herein.

In some embodiments, ring A is a phenyl linked to the Z⁵ carbon and thecompounds includes at least one of: Y is a bond; R¹ is apara-substituent halogen, alkoxy, hydroxyl, or amine when X is SO orSO₂; R² is a halogen or alkoxy substituent on the Z³ carbon when X is SOor SO₂; R² is a alkyl ester or is not a substituent on Z³ carbon orhydrogen; R² is not a substituent on Z³ carbon or hydrogen; m is greaterthan 1; and n is greater than 1.

In some embodiments, ring A is linked to the Z⁶ carbon.

In some embodiments, R² is a halogen or alkoxy substituent on the Z³carbon when X is NH, O, CH₂, CH₂CH₂, N═N, SO or SO₂.

In some embodiments, R¹ is a para-substituent halogen, alkoxy, hydroxyl,or amine when X is NH, O, CH₂, CH₂CH₂, N═N, SO or SO₂.

In some embodiments, R¹ is not only a para-substituent orortho-substituent when X is S and R² is a substituent on the Z³ carbonor a hydrogen and R3 is hydrogen or alkyl.

In some embodiments, ring A is phenyl liked to the Z⁵ carbon, thestructure is characterized by at least one of: Y is a bond; R¹ is not apara-substituent that is halogen, hydroxyl, or alkoxy or anortho-substituent that is an amine or halogen; R² is not only a Z³substituent of halogen or alkoxy; R² is a Z⁴ substituent; R³ is asubstituent other than hydrogen or straight chain alkyl; X is NH, O,CH₂, CH₂CH₂, N═N, SO or SO₂; Z⁵ carbon and Z⁶ carbon have differentsubstituents; m is at least 2; or n is at least 2.

In some embodiments, the structure is characterized by at least one of:Y is a bond; ring A is a benzothiazolyl or naphthyl having at least oneR¹ substituent; ring A is a naphthyl linked to Y through the Cl carbon(e.g., carbon adjacent to a carbon common to both rings); R¹, R², or R³includes an aryl; at least one R¹ is a meta-substituent or anortho-substituent other than amine; at least one R² is a substituent ona carbon other than the Z³ carbon; X is NH, O, CH₂, CH₂CH₂, N═N, SO orSO₂; m is at least 2; or n is at least 2.

In some embodiments, ring A is linked to the Z⁶ carbon and Z⁵ includesR³ being a substituent other than hydrogen or alkyl when ring A is aphenyl.

In some embodiments, the compound has a structure of Formula B orderivative thereof, salt thereof, or stereoisomer thereof, or having anychirality at any chiral center, or tautomer, polymorph, solvate, orcombination thereof:

In Formula B, wherein R is not

when the X, Y, Ring A, R¹, and n are identical to each other or whenring A is a phenyl and R¹ is a halogen para-substituent. Here, the twosubstituents are different.

In some embodiments, the compound having a structure of Formula C orderivative thereof, salt thereof, or stereoisomer thereof, or having anychirality at any chiral center, or tautomer, polymorph, solvate, orcombination thereof:

In Formula C, each R¹ is different when both substituents include thesame X, same Y, same n, ring A as a phenyl and R¹ is a halogenpara-substituent. Here, the two substituents can be the same except forwhen include the same X, same Y, same n, ring A as a phenyl and R¹ is ahalogen para-substituent. Otherwise, the two substituents can be thesame or can be different from each other.

In some embodiments, the compound has a structure of Formula D orderivative thereof, salt thereof, or stereoisomer thereof, or having anychirality at any chiral center, or tautomer, polymorph, solvate, orcombination thereof:

In some embodiments of Formula D, the structure excludes at least oneof: R^(1C) being a halogen, hydroxyl, or alkoxy when rest of R groupsare hydrogen; R³ is an alkyl; R^(1C) and R^(2B) each independently beinga halogen, hydroxyl, or alkoxy when rest of R groups are hydrogen;R^(1A) and R^(2B) each independently being a halogen, when rest of Rgroups are hydrogen; R^(1A) being an amine and R^(2B) being a halogen,when rest of R groups are hydrogen; R^(2B) being a halogen, hydroxyl, oralkoxy when rest of R groups are hydrogen; or X is S.

In some embodiments of Formula D, the structure includes at least oneof: R^(1C) being halogen and R^(2C) being halogen; R^(1A), R^(1C), andR^(1E) each being a non-hydrogen substituent; R^(1B), R^(1C), and R^(1D)each being a non-hydrogen substituent; R^(1A) being halogen or hydroxyl;R^(1A) being a fluorocarbon; R^(1A) being an alkyl; R^(1A) being anon-hydrogen substituent when R³ is an alkyl; R^(1A) being anon-hydrogen substituent when R^(2B) is a hydroxy or alkoxy; R^(2B)being an alkylester; R^(2B) and R^(2c) each being a non-hydrogensubstituent; R^(2A) and R^(2c) each being a non-hydrogen substituent;R^(2B) and R^(2D) being a non-hydrogen substituent; R^(2B) being afluorocarbon; R³ being an alkynol (e.g., alkyl alcohol); each of R^(1A)through R^(1E) being a non-hydrogen substituent; or X is NH, O, CH₂,CH₂CH₂, N═N, SO or SO₂.

In some embodiments, the novel compounds can be any of the compounds ofthe formulae provided herein.

In some embodiments, the novel compounds can be included in compositionthat includes: the novel compound of one of the embodiments; and acarrier having the compound. In some aspects, the carrier is apharmaceutically acceptable carrier.

In some embodiments, the novel compounds can be included in an articleof manufacture that includes: the novel compound of one of theembodiments; and a material having the compound. In some aspects, thematerial includes the compound within a body of the material. In someaspects, the material includes the compound on a surface of thematerial.

In some embodiments, Formula C2D includes: R^(1A) being F, CF₃, CH₃,carboxy (e.g., carboxylic acid C(O)OH), or methanol; R^(1C) being H orF; R^(2B) being Br, CH₃, or CF₃; R³ being methyl, ethyl, isopropyl, ortert-butyl; R⁴ is H; the rest of the R groups are H; and X is NH, O,CH₂, CH₂CH₂, N═N, S, SO, or SO₂.

In some embodiments, each R¹, R², R³ and/or R⁴ is independently asubstituent as described herein that further includes an end group thatis functional to function as a conjugation moiety. That is, anysubstituent recited herein can further include a conjugation moiety at aterminal end, which conjugation moiety can be used to link theantimicrobial to a substrate or any material. The examples ofconjugation moieties can include alkoxy silicones (e.g., triethoxysilicon), biotin, carboxylic acid, amine, halide, or any other commonreactive chemical moiety that can be used to form a covalent bond with asubstrate. In some aspects, only R² or R³ may be a substituent asdescribed herein that further includes an end group that is functionalto function as a conjugation moiety. In some aspects, R⁴ is hydrogen.

In some embodiments, each R¹, R², R³ and/or R⁴ is independently asubstituent as described herein that further includes a polymer, such asa water soluble polymer, such as a poly ether (e.g., PEG). The polymercan be attached to the ring structure, within the substituent, or as aterminal portion of the substituent. For example, the antimicrobials canbe PEGylated for improved water solubility. In some aspects, only R² orR³ may be a substituent as described herein that further includes apolymer. In some aspects, R⁴ is hydrogen.

In some embodiments, an antimicrobial compound having a structure ofFormula 1 or other formulae, or derivative thereof, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof: wherein ring A isa cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or polycyclecombination thereof; X is NH, O, CH₂, CH₂CH₂, N═N, S, SO, or SO₂; Y is alinker or bond; Z is CH, CR², or N; Z¹ is C or N to form animidazopyridine; each Z², Z³, or Z⁴ is independently CH, CR², or N; eachZ⁵ or Z⁶ is C or CH; each R¹, R², and R³ is independently a substituent;m is 0, 1, 2, 3, or 4; and n is 0 or a positive integer, wherein atleast one R¹, R², R³ and/or R⁴ independently includes —R⁵-R⁶-R⁷,wherein: R⁵ is O, NH, or a saturated or unsaturated hydrocarbon spacerof C₀-C₁₀; R⁶ is a functional linker; R⁷ is a PEG or conjugation moiety.

For example, FIG. 4 shows a reaction scheme for the above R⁶ functionalgroups that can be reacted with a group having a PEG or a conjugationgroup, such as R⁷. As a result, Fig. shows an example of at least oneR¹, R², R³ and/or R⁴ that independently includes —R⁶-R⁷, wherein: R⁶ isa functional linker and R⁷ is a PEG or conjugation moiety. For example,the —R⁷ can include the following structure that has a PEG.

In some embodiments, at least one R¹, R², R³ and/or R⁴ independentlyincludes —R⁵-R⁶, wherein: R⁵ is O, NH, or a saturated or unsaturatedhydrocarbon spacer of C₀-C₁₀; R⁶ is an end group that is functional foruse in PEGylation. Here, the R⁶ is capable of reacting with and beingconjugated to a PEG or conjugation moiety as R⁷. For example, the R⁶ canbe at least one of the following groups:

In some embodiments, at least one R¹, R², R³ and/or R⁴ independentlyincludes —R⁵-R⁸, wherein: R⁵ is O, NH, or a saturated or unsaturatedhydrocarbon spacer of C₀-C₁₀; R⁸ is an end group that is non-functionalfor PEGylation. For example, the R⁸ can be at least one of the followinggroups:

In some embodiments, each R¹, R², R³ and/or R⁴ independently can includea diazirine group, such as an alkyl diazirine. An example is3-isopropyl-3-methyl-3H-diazirine.

In some embodiments, R² or R³ includes a terminal alkoxy silicone group.The alkoxy silicon can be a di-alkoxy silicon or tri-alkoxy silicone.For example, the alkoxy silicone can be triethoxy silicone. An exampleof the triethoxy silicon-containing substituent is provided as follows:

In some embodiments, the ring A of the formulae provided herein caninclude a thiadiazole or a thiazole, which can be substituted with an R¹group as defined herein. The R1 group can be on any possible atom of thethiadiazole or thiazole. The thiadiazole and thiazole structures forring A are shown below.

For example, the thiazole and thiadiazole for ring A with the R¹substituent can be present as follows:

In some embodiments, the compounds can be selected from the group of(structure name (Compound No.)):3-((4-bromophenyl)thio)-6-fluoro-1H-indole (172A);2-((4-bromophenyl)thio)-3-methyl-1H-indole (172B); methyl3-((4-bromophenyl)thio)-1H-indole-5-carboxylate (172G);5-bromo-3-((4-bromophenyl)sulfinyl)-1H-indole (172I);5-bromo-3-((4-bromophenyl)sulfonyl)-1H-indole (172J);6-bromo-3-((4-bromophenyl)thio)-1H-indole (174A);5,6-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AB);5,7-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AC);5-bromo-3-((perchlorophenyl)thio)-1H-indole (174AD);4,6-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AE);5-bromo-3-((4-bromophenyl)thio)-6-chloro-1H-indole (174AF);5-bromo-3-((2,4,6-trichlorophenyl)thio)-1H-indole (174AG);5-bromo-3-((3,4,5-tribromophenyl)thio)-1H-indole (174AH);2-((5-bromo-1H-indol-3-yl)thio)phenol (174AI);5-bromo-3-((2-chlorophenyl)thio)-1H-indole (174AJ);3-((2-aminophenyl)thio)-2-methyl-1H-indol-5-ol (174AK);3-((1H-indol-3-yl)thio)-5-bromo-1H-indole (174AL);3-((4-bromophenyl)thio)imidazo[1,2-a]pyridine (174AN);3-((2-hydroxyphenyl)thio)-2-methyl-1H-indol-5-ol (174AO);3-((2-hydroxyphenyl)thio)-1H-indol-5-ol (174AP);2-((5-methoxy-1H-indol-3-yl)thio)phenol (174AQ);3-((2-bromophenyl)thio)-1H-indol-5-ol (174AR);3-((2-bromophenyl)thio)-5-methoxy-1H-indole (174AS);(2-((5-bromo-1H-indol-3-yl)thio)phenyl)methanol (174AT);5-bromo-3-((2-fluorophenyl)thio)-1H-indole (174AU);5-bromo-3-((2-(trifluoromethyl)phenyl)thio)-1H-indole (174AV);3-((2-bromophenyl)thio)-5-(trifluoromethyl)-1H-indole (174AX);5-bromo-3-(o-tolylthio)-1H-indole (174AY);5-bromo-3-((2-bromophenyl)thio)-2-methyl-1H-indole (174AZ);4-bromo-3-((4-bromophenyl)thio)-1H-indole (174D);3-((4-bromophenyl)thio)-5-fluoro-1H-indole (174E);5-bromo-3-(naphthalen-1-ylthio)-1H-indole (174G);7-bromo-3-((4-bromophenyl)thio)-1H-indole (174H);5-bromo-3-((3-bromophenyl)thio)-1H-indole (174N);5-bromo-3-((4-bromobenzyl)thio)-1H-indole (174O);3-([1,1′-biphenyl]-4-ylthio)-5-bromo-1H-indole (174R);5-bromo-3-((2,3-dichlorophenyl)thio)-1H-indole (174T);5-bromo-3-((2,4-dichlorophenyl)thio)-1H-indole (174V);5-bromo-3-((3,4-dichlorophenyl)thio)-1H-indole (174W);5-bromo-2-((5-bromo-1H-indol-3-yl)thio)aniline (174X);3-((5-bromo-1H-indol-3-yl)thio)aniline (174Y);2-((5-(trifluoromethyl)-1H-indol-3-yl)thio)phenol (177A);4-((5-(trifluoromethyl)-1H-indol-3-yl)thio)phenol (177B);2-((5-(trifluoromethyl)-1H-indol-3-yl)thio)aniline (177C);3-((2-fluorophenyl)thio)-5-(trifluoromethyl)-1H-indole (177D);3-((2-bromophenyl)thio)-5-fluoro-1H-indole (177E);5-(trifluoromethyl)-3-((2-(trifluoromethyl)phenyl)thio)-1H-indole(177F); 3-((2-ethylphenyl)thio)-5-(trifluoromethyl)-1H-indole (177G);(5-bromo-3-((2-bromophenyl)thio)-1H-indol-2-yl)methanol (177H);(3-((2-ethylphenyl)thio)-5-(trifluoromethyl)-1H-indol-2-yl)methanol(177I);N-((3-((4-hydroxyphenyl)thio)-1H-indol-5-yl)methyl)-4-(triethoxysilyl)butanamide(156SI); and/or3-((2-aminophenyl)thio)-5-bromo-N-(3-(triethoxysilyl)propyl)-1H-indole-2-carboxamide(174SI), and combinations thereof.

In some aspects, 4-(1H-indol-3-yl-sulfanyl) phenol and its closederivatives (e.g., para R¹ hydroxyl substituent) are specificallyomitted. In some aspects, the omitted compounds have an R¹ hydroxyl inthe para position. In some aspects, the omitted compounds have an R¹hydroxyl in any position. In some aspects, the included compoundsinclude a R², R³, or R⁴ substituent other than hydrogen with R¹ is ahydroxyl, such as the para position.

In some embodiments, the compounds exclude the following compounds:4-((1H-indol-3-yl)thio)phenol (156I); 3-((4-bromophenyl)thio)-1H-indole(156K); 3-((4-methoxyphenyl)thio)-1H-indole (1560);2,3-bis((4-bromophenyl)thio)-1H-indole (156P);3-((4-bromophenyl)thio)-2-methyl-1H-indole (172C);5-bromo-3-((4-bromophenyl)thio)-1H-indole (172D);3-((4-bromophenyl)thio)-5-methoxy-1H-indole (172E);5-bromo-3-(phenylthio)-1H-indole (174AA);3-((4-bromophenyl)thio)-5-chloro-1H-indole (174C);5-bromo-3-((2-bromophenyl)thio)-1H-indole (174I);5-bromo-3-((4-chlorophenyl)thio)-1H-indole (174J);3-(benzylthio)-5-bromo-1H-indole (174K);2-((5-bromo-1H-indol-3-yl)thio)benzo[d]thiazole (174L);2-((5-bromo-1H-indol-3-yl)thio)aniline (174M);5-bromo-3-((4-fluorophenyl)thio)-1H-indole (174P);5-bromo-3-((4-methoxyphenyl)thio)-1H-indole (174Q);5-bromo-3-(naphthalen-2-ylthio)-1H-indole (174S);3-((4-bromophenyl)thio)-1H-indole (174U);4-((5-bromo-1H-indol-3-yl)thio)aniline (174Z); and combinations thereof.While these compounds can be used in the methods, they are specificallyexcluded from some embodiments of compounds and compositions.

In some embodiments, the compounds (and the methods) can exclude thefollowing compounds: 3-(phenylthio)-1H-indole (156L);3-(pyridin-2-ylthio)-1H-indole (156M); 2-((1H-indol-3-yl)thio)benzoicacid (156N); 3-((4-bromophenyl)thio)-1H-pyrrolo[2,3-b]pyridine (172F);ethyl 3-((4-bromophenyl)thio)-1H-indole-2-carboxylate (172H);3-((4-bromophenyl)thio)-1-methyl-1H-indole (174B); and combinationsthereof. In some aspects, these compounds are specifically excluded fromthe inventive compounds, compositions, and methods.

In some embodiments, the compounds of this section that are not indictedto be omitted or excluded in any way can be used in methods fortreating, preventing, or inhibiting a microbial infection.

In some embodiments, a method of inhibiting microbes (e.g., bacteria,fungi, or virus) can include contacting a microbe (e.g., pathogenic)with the compound such that the microbe is selectively inhibited. Insome aspects, the compound is any compound recited herein that is notomitted or excluded.

EXAMPLES

A library of antimicrobial bacterial extracts were tested for antifungalactivity against T. rubrum. The compounds provided herein emerged as themost potent. Targeted potency against pathogenic microbes was desired,and the compounds demonstrated significantly less potency against skincommensals M. furfur, S. epidermidis, and Micrococcus sp. Subsequentpurification using bioassay guided fractionation, HPLC, and LC-MSproduced a potent and pure compound from 8 liters of CFD-110 extract.NMR was used to determine the molecular structure of CFD-110.

Generally, the compounds were synthesized using the method as previouslydescribed [Tetrahedron 71 (2015) 8885-8891]. Briefly, a mixture ofindole (1 eq.), 4-hydroxythiophenol (1 eq.) and TBHP (1 eq.) weredissolved in MeCN at 60° C. in a flask, then iodine (0.2 eq.) was added.The reaction proceeded under an air atmosphere for 0.5-1.0 h untilcomplete consumption of starting material as monitored by TLC. Thereaction mixture was quenched by the addition of saturated aqueousNa₂S₂O₃ and then extracted with EtOAc. The combined organic layer wasconcentrated under vacuum and the crude product was purified byprep-HPLC to produce compound CFD-110 (90% yield).

The Table 1 shows selectivity of CFD-174M, CFD-156I and CFD-156K againstpathogens and skin commensals. Table 9 also shows the selectivity index(SI) for various compounds using B. subtilis MICs.

Table 2 shows the MBC (minimum bactericidal concentration) and MFC(minimum fungicidal concentration) of some of the antimicrobialcompounds with Bacillus subtilis, Bacillus thuringiensis, Burkholderiacenocepacia, Burkholderia thailandensis, Candida glabrata, Trichophytonrubrum (Castellani Sabouraud), and Francisella tularensis subsp.Holarctica Strain LVSR NR-597.

Table 3 shows the MIC values for Staphylococcus aureus with VSSA(Vancomycin sensitive S. aureus), VRSA (Vancomycin resistant S. aureus),and MRS A (Methicillin resistant S. aureus).

Table 4 shows the MIC values for Bacillus subtilis strains.

Table 5 shows the MIC values for Bacillus thuringiensis strains.

Table 6 shows the MIC values for TV. gonorrhoeae strains.

Table 7 shows the MIC values for Candida sp. with species C. glabratastrains and C. albicans strains.

Table 8 shows the MIC values for Francisella tularensis strains.

Table 10 shows an experimental protocol for studies for toxicity of theantimicrobial compounds in mice, where the dosing route, dose, dosingsolution concentration, and dosing volume are described. The vehicle is40% PEG300 solution in 0.9% NaCl. In Table 10, Compound 1 is Compound174AU, Compound 2 is Compound 174AZ, and Compound 3 is Compound 174AI.The mice had an average weight of 22-23 grams and were 6-week-old Balb/cmice. Table 11 shows the result of the body weight over 7 days. Asshown, these antimicrobial compounds did not have significant toxicityas evidenced by the weight staying consistent with small reductions.Thus, the compounds are useful for in vivo antimicrobial administration.

Additionally, the antimicrobial compounds were analyzed forcytotoxicity. The compounds underwent cytotoxicity testing in the HepG2liver cell line, and some of the best compounds based on selectivityindex moved into the human HepaRG primary-like cell line for furthercytotoxicity testing in more predictive cells with a natural drugmetabolism enzyme (DME) profile. We utilized the standard MTT assay(Promega CellTiter 96) and GraphPad Prism 7 software to determine EC50values for each analogue. Briefly, 20,000 HepG2 cells in 200 μl of theATCC recommended media were seeded in each well of a 96-well plate witha moisture barrier created in the outermost wells. The cells wereallowed to attach overnight at 37° C., and then observed under phasecontrast microscopy for proper morphological characteristics. If cellsappeared healthy and attached, test compounds were added in 7concentrations from 1-64 μg/ml (n=3) from freshly prepared DMSO stockplates. The cells were incubated for 48 h and then stained with[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)] andincubated at 37° C. for 4 h. Once incubations were complete, thespectrophotometric absorbance of the samples was measured at awavelength of 595 nm. Acetaminophen EC50 served as the positive controland 1% DMSO samples are considered negative control and are used asreference for subsequent IC50 calculations. For the HepaRG assay, NoSpinHepaRG™ cells (Lonza, cat #NSHPRG) were thawed and plated with 20,000cells per well. They were allowed to attach for 4 h (optimal DME profileper Lonza's testing) before dosing following the identical protocol asabove. Table 9 below provides results for the EC50.

Additionally, an extensive study to explore the mechanism of action(MOA) has revealed that the series likely has 2 MOAs with varyingdegrees of each in different analogues. Fluorescence microscopy andradiolabeling studies have clearly shown cell wall synthesis inhibitionas a MOA for the series of compounds with Compound No. 174I.Transcriptomic and metabolic studies have demonstrated branched chainamino acid biosynthesis inhibition as another MOA for 174I and 174M. Thecombination of cell wall synthesis inhibition and BCAA synthesisinhibition is the novel, dual mechanism behind our potent,broad-spectrum compounds. Multiple MOAs are ideal for combating AMRbecause the pathogen has to evolve 2 resistance mechanismssimultaneously to survive treatment with a dual MOA antimicrobial (e.g.,antibiotic).

Cell wall permeability/disruption measured by SYTOX green fluorescenceassay which emits only when able to enter the cell and bind DNA; FM 4-64dye (red) which aggregates in disrupted cell walls. FIG. 1A shows SYTOXassay on S. aureus with analogue 174I. Concentrations are relative tothe MIC, and a clear dose-dependent increase in permeability isdemonstrated by the data. MEL is the positive control melittin whichpermeabilizes cells. FIG. 1B shows SYTOX assay with B. cenocepaciademonstrating cell permeabilization. FIG. 1C shows an image with FM 4-64stained B. subtilis cells imaged with a fluorescence microscope. Thearrows point to areas of aggregation and cell wall disruption seen inboth analogue 174I and melittin treated cells only.

FIG. 2A-2B show the macromolecular synthesis assay dose-response curvedemonstrating substantial cell wall synthesis inhibition with 174I (FIG.2A) compared to vancomycin (FIG. 2B).

FIG. 2C shows the SYTOX assay indicates no permeabilization of HepG2cells by up to 4×MIC of analogues 174I and 174M. Additionally, data withHepG2 cells also indicates no cell membrane damage by the analogues byminimal staining in treated cells.

FIG. 3 shows a dose-dependent upregulation RNAseq data expressed in foldincrease based on RNA sequencing experiments. The increase in thesegenes' expression suggests that when these analogues are given to thecells, a pathway is triggered which causes increased transcription ofthese genes. It could be that the compounds are inhibiting this pathwayby binding a protein in the pathway and a feedback mechanism detectsreduced pathway products or build-up of intermediates leading toincreased expression to combat these effects. The branched chain aminoacid synthesis pathway gene, ILVB is highly upregulated. ILVB'sinhibition causes a build-up of 2-ketobutyrate which can be toxic atvery high concentrations. We demonstrated a synergy between 174M and2-ketobutyrate as shown in FIG. 3.

FIGS. 5A-5B show selectivity for inhibiting pathogenic microbes overcommensal microbes on polyester fabric. FIG. 5A shows that Compound 156Iselectively inhibits pathogens T. rubrum over commensal microbes R.mucosa and S. epidermidis. FIG. 5B shows that Compound 156K inhibits thepathogens T. rubrum and S. Aureus over commensal microbes R. mucosa andS. epidermidis

Additionally, an experiment was performed to determine synergisticeffect of the compounds with 2-ketobutyrate compared to those oftetracycline with 2-ketobutyrate. Without ketobutyrate, the MIC ofCompound 174M is 3.124 μg/mL and the MIC of tetracycline is 6.25. With200 μg/mL 2-ketobutyrate, the MIC of 174M dropped to 0.781 and with 800μg/mL 2-ketobutyrate, the MIC of 174M dropped to less than 0.39.However, the MIC for tetracycline did not change with eitherconcentration of 2-ketobutyrate. Thus, at least Compound 174M provides asynergistic effect with 2-ketobutyrate. It is expected that the othercompounds, especially those similar to Compound 174M, also can have asynergistic effect with 2-ketobutyrate.

Definitions

As used herein, the term “infection” is encompassed by the term“colonization” and includes disease associated colonization and/orundesirable colonization.

In some embodiments the treatment, mitigation, or prevention forParkinson's disease in a subject in need thereof comprises physicalremoval or reduction (e.g. debridement) of the microbial infection.

The term “administered,” “administering” or “administration” includesroutes of administration which allow the antimicrobial agents to performtheir intended function(s) of preventing, mitigating, or treatingdisease in a subject. Examples of routes of administration includeparenteral (e.g., subcutaneous, intramuscular, intraorbital,intracapsular, intraspinal, intrastemal, intravenous, intradermal,intraperitoneal, intraportal, intra-arterial, intrathecal, transmucosal,intra-articular, and intrapleural,), transdermal, topical, epidural, andmucosal injection or infusion, as well as oral, intranasal, inhalation,insufflation, pulmonary, and rectal administration Examples of preferredroutes of administration which may be used include injection, topical,oral, intranasal, subcutaneous, intravenous, inhalation and transdermal.

In some embodiments, the antimicrobial agent is administered incombination with a pharmaceutically acceptable carrier. Examples of suchcarriers include those suitable for injection, topical, oral,intranasal, subcutaneous, intravenous, inhalation and/or transdermaladministration.

When used herein, the term “therapeutically effective amount” or“effective amount” includes an amount of the therapeutic or treatmentcomposition that provides a prophylactic or therapeutic benefit in thetreatment, prevention, or management of a disease or a symptom of adisease. The therapeutically effective amount may treat a disease orcondition, a symptom of disease, or a predisposition toward a disease,with the purpose to cure, heal, alleviate, relieve, alter, remedy,ameliorate, improve, or affect the disease, the symptoms of disease, orthe predisposition toward disease. The term “therapeutically effectiveamount” or “effective amount” of the antimicrobial agent includes anamount of the antimicrobial agent that is sufficient in treating,mitigating, or preventing a microbial infection, such as jock itch orathlete's foot or other.

The dosage ranges for the administration are those that produce thedesired effect. Generally, the dosage will vary with the age, weight,condition, and sex of the patient, and the extent of disease. A personof ordinary skill in the art, given the teachings of the presentspecification, may readily determine suitable dosage ranges.

As used herein, the term “antimicrobial agent” is any substance that hasa significant biocidal and/or biostatic activity against a fungus foruse in the treatment, mitigation, or prevention of disease. In someembodiments, the antimicrobial agent inhibits the growth of one or moremicrobial organisms in a subject receiving said agent. In someembodiments, the antimicrobial agent kills one or more microorganisms ina subject receiving said agent.

In some embodiments, the antimicrobial agent is a substance that has abiocidal and/or biostatic activity for microbes. In further embodiments,the antimicrobial agent is a substance that has a biocidal and/orbiostatic activity that is relatively specific and selective forpathogenic microbes over commensal microbes.

By “substituted” as in “substituted alkyl,” “substituted aryl,” and thelike, as alluded to in some of the definitions provided herein, is meantthat in the alkyl, aryl, or other moiety, at least one hydrogen atombound to a carbon (or other) atom is replaced with one or morenon-hydrogen substituents.

In addition, the aforementioned functional groups may, if a particulargroup permits, be further substituted with one or more additionalfunctional groups or with one or more hydrocarbyl moieties such as thosespecifically enumerated above. Analogously, the above-mentionedhydrocarbyl moieties may be further substituted with one or morefunctional groups or additional hydrocarbyl moieties such as thosespecifically enumerated.

When the term “substituted” appears prior to a list of possiblesubstituted groups, it is intended that the term apply to every memberof that group. For example, the phrase “substituted alkyl, alkenyl, andaryl” is to be interpreted as “substituted alkyl, substituted alkenyl,and substituted aryl.” Analogously, when the term“heteroatom-containing” appears prior to a list of possibleheteroatom-containing groups, it is intended that the term apply toevery member of that group. For example, the phrase“heteroatom-containing alkyl, alkenyl, and aryl” is to be interpreted as“heteroatom-containing alkyl, heteroatom-containing alkenyl, andheteroatom-containing aryl.”

As used herein, “optionally substituted” indicates that a chemicalstructure may be optionally substituted with a substituent group, suchas defined herein. That is, when a chemical structure includes an atomthat is optionally substituted, the atom may or may not include theoptional substituent group, and thereby the chemical structure may beconsidered to be substituted when having a substituent on the atom orunsubstituted when omitting a substituent from the atom. A substitutedgroup, referred to as a “substituent” or “substituent group”, can becoupled (e.g., covalently) to a previously unsubstituted parentstructure, wherein one or more hydrogen atoms (or other substituentgroups) on the parent structure have been independently replaced by oneor more of the substituents. The substituent is a chemical moiety thatis added to a base chemical structure, such as a chemical scaffold. Assuch, a substituted chemical structure may have one or more substituentgroups on the parent structure, such as by each substituent group beingcoupled to an atom of the parent structure. The substituent groups thatcan be coupled to the parent structure can be any possible substituentgroup. In examples of the present technology, the substituent groups(e.g., R groups) can be independently selected from an alkyl, —O-alkyl(e.g. —OCH₃, —OC₂H₅, —OC₃H₇, —OC₄H₉, etc.), —S-alkyl (e.g., —SCH₃,—SC₂H₅, —SC₃H₇, —SC₄H₉, etc.), —NR′R″, —OH, —SH, —CN, —NO₂, or ahalogen, wherein R′ and R″ are independently H or an optionallysubstituted alkyl. Wherever a substituent is described as “optionallysubstituted,” that substituent can also be optionally substituted withthe above substituents.

The term amino refers to the overall charged or net uncharged chemicalgroup, where the R group can be a substituent, such as the substituentsdescribed herein:

The term “alkyl” or “aliphatic” as used herein refers to a branched orunbranched saturated hydrocarbon group typically although notnecessarily containing 1 to about 24 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl,and the like, as well as cycloalkyl groups such as cyclopentyl,cyclohexyl, and the like. Generally, although again not necessarily,alkyl groups herein contain 1 to about 18 carbon atoms, or 1 to about 12carbon atoms. The term “lower alkyl” intends an alkyl group of 1 to 6carbon atoms. Substituents identified as “C₁-C₆ alkyl” or “lower alkyl”contain 1 to 3 carbon atoms, and such substituents contain 1 or 2 carbonatoms (i.e., methyl and ethyl). “Substituted alkyl” refers to alkylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in whichat least one carbon atom is replaced with a heteroatom, as described infurther detail infra. If not otherwise indicated, the terms “alkyl” and“lower alkyl” include linear, branched, cyclic, unsubstituted,substituted, and/or heteroatom-containing alkyl or lower alkyl,respectively.

The terms “alkenyl” as used herein refers to a linear, branched orcyclic hydrocarbon group of 2 to about 24 carbon atoms containing atleast one double bond, such as ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl,eicosenyl, tetracosenyl, and the like. Generally, although again notnecessarily, alkenyl groups herein contain 2 to about 18 carbon atoms,or 2 to 12 carbon atoms. The term “lower alkenyl” intends an alkenylgroup of 2 to 6 carbon atoms, and the specific term “cycloalkenyl”intends a cyclic alkenyl group, or having 5 to 8 carbon atoms. The term“substituted alkenyl” refers to alkenyl substituted with one or moresubstituent groups, and the terms “heteroatom-containing alkenyl” and“heteroalkenyl” refer to alkenyl in which at least one carbon atom isreplaced with a heteroatom. If not otherwise indicated, the terms“alkenyl” and “lower alkenyl” include linear, branched, cyclic,unsubstituted, substituted, and/or heteroatom-containing alkenyl andlower alkenyl, respectively.

The term “alkynyl” as used herein refers to a linear or branchedhydrocarbon group of 2 to 24 carbon atoms containing at least one triplebond, such as ethynyl, n-propynyl, and the like. Generally, althoughagain not necessarily, alkynyl groups herein contain 2 to about 18carbon atoms, or 2 to 12 carbon atoms. The term “lower alkynyl” intendsan alkynyl group of 2 to 6 carbon atoms. The term “substituted alkynyl”refers to alkynyl substituted with one or more substituent groups, andthe terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer toalkynyl in which at least one carbon atom is replaced with a heteroatom.If not otherwise indicated, the terms “alkynyl” and “lower alkynyl”include linear, branched, unsubstituted, substituted, and/orheteroatom-containing alkynyl and lower alkynyl, respectively.

The term “alkoxy” as used herein intends an alkyl group bound through asingle, terminal ether linkage; that is, an “alkoxy” group may berepresented as —O-alkyl where alkyl is as defined above. A “loweralkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms,and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy,t-butyloxy, etc. Substituents identified as “C₁-C₆ alkoxy” or “loweralkoxy” herein contain 1 to 3 carbon atoms, and such substituentscontain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent containing a single aromatic ring or multiplearomatic rings that are fused together, directly linked, or indirectlylinked (such that the different aromatic rings are bound to a commongroup such as a methylene or ethylene moiety). Examples of aryl groupscontain 5 to 20 carbon atoms, and aryl groups contain 5 to 14 carbonatoms. Exemplary aryl groups contain one aromatic ring or two fused orlinked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether,diphenylamine, benzophenone, and the like. “Substituted aryl” refers toan aryl moiety substituted with one or more substituent groups, and theterms “heteroatom-containing aryl” and “heteroaryl” refer to arylsubstituent, in which at least one carbon atom is replaced with aheteroatom, as will be described in further detail infra. If nototherwise indicated, the term “aryl” includes unsubstituted,substituted, and/or heteroatom-containing aromatic substituents.

The term “aryloxy” as used herein refers to an aryl group bound througha single, terminal ether linkage, wherein “aryl” is as defined above. An“aryloxy” group may be represented as —O-aryl where aryl is as definedabove. Examples of aryloxy groups contain 5 to 20 carbon atoms, andaryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groupsinclude, without limitation, phenoxy, o-halo-phenoxy, m-halo-phenoxy,p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy,2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy, and the like.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. Examplesof aralkyl groups contain 6 to 24 carbon atoms, and aralkyl groupscontain 6 to 16 carbon atoms. Examples of aralkyl groups include,without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl,4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl,4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl,p-cyclohexylphenyl, 2,7-dimethyinaphthyl, 7-cyclooctylnaphthyl,3-ethyl-cyclopenta-1,4-diene, and the like.

The term “cyclic” refers to alicyclic or aromatic substituents that mayor may not be substituted and/or heteroatom containing, and that may bemonocyclic, bicyclic, or polycyclic.

The terms “halo” and “halogen” are used in the conventional sense torefer to a chloro, bromo, and fluoro or iodo substituent.

The term “heteroatom-containing” as in a “heteroatom-containing alkylgroup” (also termed a “heteroalkyl” group) or a “heteroatom-containingaryl group” (also termed a “heteroaryl” group) refers to a molecule,linkage or substituent in which one or more carbon atoms are replacedwith an atom other than carbon, e.g., nitrogen, oxygen, sulfur,phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly,the term “heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the terms “heteroaryl” andheteroaromatic” respectively refer to “aryl” and “aromatic” substituentsthat are heteroatom-containing, and the like. Examples of heteroalkylgroups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylatedamino alkyl, and the like. Examples of heteroaryl substituents includepyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl,imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples ofheteroatom-containing alicyclic groups are pyrrolidine, morpholine,piperazine, piperidine, etc.

The term “hydrocarbyl” refers to univalent hydrocarbyl radicalscontaining 1 to about 30 carbon atoms, or 1 to about 24 carbon atoms, or1 to about 18 carbon atoms, or about 1 to 12 carbon atoms, includinglinear, branched, cyclic, saturated, and unsaturated species, such asalkyl groups, alkenyl groups, aryl groups, and the like. “Substitutedhydrocarbyl” refers to hydrocarbyl substituted with one or moresubstituent groups, and the term “heteroatom-containing hydrocarbyl”refers to hydrocarbyl in which at least one carbon atom is replaced witha heteroatom. Unless otherwise indicated, the term “hydrocarbyl” is tobe interpreted as including substituted and/or heteroatom-containinghydrocarbyl moieties.

The atoms recited herein include their isotopes. For example, the term“hydrogen” specifically includes the isotopes thereof, such asdeuterium. Thus, deuteration of the compounds is contemplated.

All other chemistry terms are defined as known in the art.

One skilled in the art will appreciate that, for this and otherprocesses and methods disclosed herein, the functions performed in theprocesses and methods may be implemented in differing order.Furthermore, the outlined steps and operations are only provided asexamples, and some of the steps and operations may be optional, combinedinto fewer steps and operations, or expanded into additional steps andoperations without detracting from the essence of the disclosedembodiments.

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from its spirit and scope, as will be apparentto those skilled in the art. Functionally equivalent methods andapparatuses within the scope of the disclosure, in addition to thoseenumerated herein, will be apparent to those skilled in the art from theforegoing descriptions. Such modifications and variations are intendedto fall within the scope of the appended claims. The present disclosureis to be limited only by the terms of the appended claims, along withthe full scope of equivalents to which such claims are entitled. It isto be understood that this disclosure is not limited to particularmethods, reagents, compounds compositions or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular embodimentsonly, and is not intended to be limiting.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). Furthermore, in thoseinstances where a convention analogous to “at least one of A, B, and C,etc.” is used, in general such a construction is intended in the senseone having skill in the art would understand the convention (e.g., “asystem having at least one of A, B, and C” would include but not belimited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, or C” wouldinclude but not be limited to systems that have A alone, B alone, Calone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). It will be further understood by those withinthe art that virtually any disjunctive word and/or phrase presenting twoor more alternative terms, whether in the description, claims, ordrawings, should be understood to contemplate the possibilities ofincluding one of the terms, either of the terms, or both terms. Forexample, the phrase “A or B” will be understood to include thepossibilities of “A” or “B” or “A and B.”

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” and the like include the number recited andrefer to ranges which can be subsequently broken down into subranges asdiscussed above. Finally, as will be understood by one skilled in theart, a range includes each individual member. Thus, for example, a grouphaving 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, agroup having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells,and so forth.

From the foregoing, it will be appreciated that various embodiments ofthe present disclosure have been described herein for purposes ofillustration, and that various modifications may be made withoutdeparting from the scope and spirit of the present disclosure.Accordingly, the various embodiments disclosed herein are not intendedto be limiting, with the true scope and spirit being indicated by thefollowing claims.

All references recited herein are incorporated herein by specificreference in their entirety.

Tables:

TABLE 1 Selectivity of CFD-174M, CFD-156I and CFD-156K against pathogensand skin commensals Pathogens MIC Skin Commensals-MIC μg/mL μg/mLSelectivity Cytotoxicity Staphylococcus Trichophyton RoseomonasStaphylococcus Pathogens HepaRG Selectivity aureus rubrum mucosaepidermidis to EC50 Index Compounds (SA) (TR) (RM) (SE) commensal μg/mL(SI) CFD-174M 2.0 0.9 >50 16 80->55.5 85 43->85 CFD-156K 3.1 0.9 >50 >5016->55.5 32 10->32 CFD-156I 16 >64 >64 >4 >20 >1

TABLE #2 Bacillus Francisella subtilis Bacillus BurkholderiaTrichophyton tularensis (Ehrenberg 1835) thuringiensis Burkholderiathailandensis Candida rubrum subsp. Holarctica Comp. Cohn 1872 Berlinercenocepacia Brett et al glabrata CastellaniSabouraud Strain LVSR No.NRRL: B-571 ATCC: 10792 NRRL: B-59561 ATCC: 700388 #584 ATCC: 28188NR-597 (μg/mL) MIC MBC MIC MBC MIC MBC MIC MBC MIC MFC MIC MIC 156I 2040 20 40 50 150  50 100 50 — 12.05 20 156O 6.25 12.5 6.25 >50 >50 — — —50 — 3.19 3.13 156P 12.5 >50 3.13 >50 >50 — — — >50 — 6.11 >50 172A1.56 >50 1.56 1.56 >50 — >50 — 1.56 3.13 9.52 0.78 172B 6.25 25 6.2525 >50 — — — 50 — 15.6 3.13 172C 1.56 6.25 1.56 1.56 >50 — >50 —3.13 >50 1.98 1.56 172D 1.25 5 1.25 10 100 >150  100 >150  >50 — 1.181.25 172E 1.56 6.25 1.56 12.5 >50 — >50 — 6.25 >50 2.08 0.78 172G 11.345 11.3 >45 >45 — — — >50 — 18.1 — 172I 10 10 10 40 >40 — — — >40 — 9.9220 172J 3.13 6.25 1.56 3.13 >50 — >50 — >50 — 10.3 6.25 174A 3.13 6.253.13 3.13 >50 — >50 — 12.5 — — 1.56 174AA 4 16 8 16 >50 — >50 — 3.136.25 — 4 174AB 4 16 2 8 >50 — >50 — 3.13 — — 4 174AC 8 16 8 50 >50 — >50— 25 — — — 174AD 16 50 32 >50 >50 — >50 — >50 — — — 174AE 2 4 2 >50 >50— >50 — 25 — — 4 174AF 4 50 2 4 >50 — >50 — >50 — — 4 174AG 4 >504 >50 >50 — >50 — 6.25 >50 — — 174AH 8 >50 8 >50 >50 — >50 — >50 — — —174AI 0.78 6.25 0.78 >50 12.5 >50   12.5 >50 6.25 25 — 2 174AJ 0.78 3.130.78 1.56 >50 — >50 — 6.25 25 — — 174AK 50 >50 >50 N/A >50 — >50 — >50 —— — 174AL 0.78 1.56 1.56 >50 >50 — >50 — 6.25 25 — — 174AN 16 — — — — —— — 50 — — — 174AO 50 — — — — — — — >50 — — 50 174AP 50 — — — — — —— >50 — — 50 174AQ 32 — — — — — — — 50 — — 16 174AR 8 — — — — — — — 50 —— 4 174AS 2 — — — — — — — >50 — — 1 174AT 8 16 8 16 — — — — 50 — — 8174AU 1 2 1 2 — — — — 3.13 50 — 0.25 174AV 1 2 1 1 — — — — 25 — — 1174AX 0.5 8 1 2 — — — — 12.5 — — 1 174AY 1 2 2 4 — — — — — — — 1 174AZ 14 1 8 — — — — >50 — — 1 174C 1.56 3.13 1.56 1.56 >50 — >50 — 3.13 — 2.111.56 174D 1.56 3.13 1.56 3.13 >50 — >50 — 3.13 — 2.38 1.56 174E 1.563.13 1.56 3.13 >50 — >50 — 3.13 — 2.01 0.78 174G 1.56 50 1.56 3.13 >50— >50 — >50 — 2.21 — 174H 3.13 >50 6.25 12.5 >50 — >50 — 12.5 — 2.383.13 174I 0.78 3.13 0.78 1.56 >50 — >50 — 3.13 >50 1.19 <0.39 174J 1.563.13 1.56 1.56 >50 — >50 — 6.25 >50 1.05 — 174K 3.13 6.25 3.13 6.25 >50— >50 — 6.25 12.5 1.98 — 174L 1.56 >50 1.56 50 >50 — >50 — >50 — >18 —174M 0.63 10 1.25 5 150 >150  150 >150  12.5 — 0.99 2.5 174N 1.25 101.25 10 50 >150   50 >150  6.25 50 <0.57 1.25 174O 3.13 >50 3.133.13 >50 — >50 — >50 — 1.24 — 174P 1.56 3.13 1.56 >50 >50 — >50 —3.13 >50 2.01 — 174Q 1.56 >50 1.56 12.5 >50 — >50 — 3.13 >50 2.08 —174R >50 N/A >50 N/A >50 — >50 — >50 — >9.50 — 174S >50 N/A >50 N/A >50— >50 — >50 — >8.82 — 174T 1.25 >10 1.25 2.5 >50 — >50 — 3.13 25 1.16 —174U >50 >10 12.5 12.5 >50 — >50 — >50 — 0.95 1.56 174V 1.25 2.5 1.252.5 >50 — >50 — 3.13 12.5 0.58 — 174W 1.25 >10 1.25 5 >50 — >50 — 25 —1.16 — 174X 1.56 >10 2.5 2.5 >50 — >50 — 6.25 6.25 0.62 — 174Y 10 >1010 >10 >50 — >50 — 25 — 3.97 — 174Z 10 >10 10 >10 >50 — >50 — 25 — 3.97— 177A 0.39 — — — 25 >50 >50 >50 >50 — — 0.78 177B 1.56 — — — 25 >50 25 >50 >50 — — 3.13 177C 0.39 — — — >50 >50 >50 >50 >50 — — 3.13 177D1.56 — — — 12.5 >50 >50 >50 25 — — 0.78 177E 1.56 — — — >50 >50 >50 >5025 — — 0.78 177F 1.56 — — — 6.25 >50 >50 >50 50 — — 1.56 177G 1.56 — —— >50 >50 >50 >50 >50 — — 0.78 177H 1.56 — — — 25 >50 >50 >50 50 — —3.13 177I 3.13 — — — >50 >50 >50 >50 >50 — — 3.13 *MBC = Minimumbactericidal concentration, MFC = Minimum fungicidal concentration

TABLE 3 Staphylococcus aureus MIC Comp. No. VSSA* VRSA* MRSA* strains(μg/mL) NR-49121 NR-49120 NK-41886 HM-467 NR-13533 NR-28983 NR-41875NR-41876 NR-41877 NR-41878 172D 1.56 1.56 1.56 12.5 1.56 1.56 3.13 1.563.13 1.56 174M 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 25 12.5 174N 1.563.13 3.13 3.13 3.13 3.13 3.13 3.13 3.13 3.13 174AI 8 8 8 16 8 8 8 8 8 8174AT 16 16 16 32 16 16 16 16 16 16 174AU 4 2 2 2 2 2 2 2 4 2 174AV 2 22 2 1 1 1 2 2 2 174AX 1 1 2 2 1 2 1 2 2 1 174AY 2 2 4 4 4 4 4 2 2 2174AZ 2 2 — — — — 4 2 — — *VSSA—Vancomycin sensitive S. aureus,VRSA—Vancomycin resistant S. aureus, MRSA—Methicillin resistant S.aureus

TABLE 4 Bacillus subtilis MIC Comp. B. subtilis strains (μg/mL) BD-594B-14322 B-41090 B-41581 B-3665 B-1985 B-571 174AB 4 2 4 2 2 4 —156K >50 >50 >50 3.13 >50 >50 >50 174M 5 2.5 5 5 10 5 0.625 174N 2.51.25 2.5 0.625 1.25 1.25 1.25 174I 3.13 3.13 3.13 3.13 3.13 3.13 3.13174AI 6.25 3.13 6.25 6.25 6.25 0.78 0.78 172D 2.5 1.25 2.5 1.25 1.251.25 1.25

TABLE 5 Bacillus thuringiensis MIC Comp. B. thuringiensis strains(μg/mL) B-23149 B-23133 B-41596 HD-268 HD-34 ATCC 10792 174AB 2 2 4 4 4— 156K >50 >50 >50 >50 >50 — 174M 1.25 0.625 1.25 1.25 2.5 0.625 174N2.5 1.25 2.5 2.5 1.25 1.25 174I 1.56 1.56 1.56 1.56 1.56 1.56 174AI 1.560.78 0.78 2.56 1.56 0.78 172D 5 1.25 2.5 2.5 2.5 1.25

TABLE 6 N. gonorrhoeae MIC N. gonorrhoeae Comp. strains (μg/mL) #167#203 #205 174I 1.56 — — 174AI <0.39 — — 172E <0.39 3.13 3.13 174AV 3.125— — 174AZ 3.125 — — 174E <0.39 1.56 1.56 174N 1.56 — — 174M 1.56 — —177A — 3.13 3.13 177C — 3.13 3.13

TABLE 7 Candida sp. MIC's C. glabrata strains C. albicans strains Comp.#584 #325 #761 #762 (μg/mL) MIC MFC MIC MFC MIC MFC MIC MFC 156I50 >50 >50 — >50 — 50 >50 172A 156 3.13 6.25 12.5 3.13 12.5 1.56 6.25174AB 3.13 — >50 — >50 — >50 — 174AE 25 — 12.5 >50 50 >50 6.25 25 174AX12.5 — >50 — 12.5 50 6.25 12.5 174D 3.13 — >50 — >50 — 3.13 12.5 174I3.13 >50 25 50 12.5 25 3.13 6.25 174M 12.5 — 25 >50 12.5 25 3.13 25 174N6.25 50 >50 — 12.5 >50 3.13 6.25 174W 25 — >50 — >50 — >50 — 174X 6.256.25 12.5 >50 12.5 >50 12.5 >50 MFC = Minimum fungicidal concentration

TABLE 8 F. tularensis BSL-3 MIC Francisella tularensis strains Comp.SCHU MA00- MO MO MO WY- Strain OR- HN- (μg/mL) S4 LVS 2987 #1 #2 #3 96100 96 63 MIC50 MIN MAX 172E 4 >8 8 5.33 3.33 8 >8 >8 8 8 8 3.33 >8174AI 4 4 1.67 1.33 1.33 2 6 6 4 2 3 1.33 6 174AU 4 2 2 1.83 1.67 2 1.58 4 2 2 1.5 8 174AV 4 4 3.67 3 2 4 4 6 4 4 4 2 6 174X 4 >8 4 2.67 2 4 38 4 4 4 2 >8 174AY 4 4 3.67 2 3.33 3.67 4 4 4 2 3.83 2 4 174AZ 4 2.67 21.33 1 2 2 4 2 2 2 1 4 174I 8 2 1.33 2 1 2 2 8 4 4 2 1 8 174M 8 2 2 21.67 4 4 >8 4 4 4 1.67 >8 174N >8 6.67 6.67 3.33 3.67 4 4 8 4 4 4 3.33>8

TABLE 9 Compound EC50 SI 174C 25.4 16.3 174D 23.2 14.9 174E 23.6 14.2174P 38.3 24.6 174V 24.8 19.8 172C 26.8 17.2 174AL 26.1 33.5 174AI 27.435.1 174AU 26.8 26.8 174AZ 25.8 25.7 174X 30.2 19.3 174J 25.3 16.2 177A24.1 61.8 177B 27.7 17.8 177C 48.2 123.6 177D 27.1 17.4 177E 31.6 20.3177F 29.8 19.1 177G 29.5 18.9 177H 31.8 20.4 177I 31.3 10.0 156K 27.6^(~)0.6 174I 25.4 32.6 174M 26.5 42.4 174N 29.5 23.6 172E 23.3 14.9 156I12.1 0.6

TABLE 10 Total Dosing Solution Dosing Group Test Dosing Animals DoseConc. Volume # Article Route N= mg/kg¹ ug/mL¹ mL/kg 1 Compound 1 IP 30.1 6.8 15 2 IP 3 1 68 15 3 IP 3 10 680 15 4 Compound 2 IP 3 0.1 6.8 155 IP 3 1 68 15 6 IP 3 10 680 15 7 Compound 3 IP 3 0.1 6.8 15 8 IP 3 1 6815 9 IP 3 10 680 15 10 Vehicle IP 3 NA NA 15 Control

TABLE 11 Animal body weight (kg) Group # Animal # Day 0 Day 1 Day 2 Day3 Day 4 Day 5 Day 6 Day 7 Group 1 99 0.026 0.024 0.025 0.025 0.025 0.0250.025 0.024 100 0.023 0.022 0.022 0.022 0.022 0.023 0.022 0.022 1010.024 0.023 0.023 0.023 0.023 0.024 0.023 0.023 Group 2 102 0.022 0.0220.022 0.022 0.023 0.023 0.023 0.024 103 0.025 0.025 0.025 0.025 0.0250.025 0.025 0.025 104 0.026 0.025 0.026 0.026 0.026 0.026 0.025 0.026Group 3 105 0.024 0.023 0.023 0.024 0.023 0.023 0.022 0.022 106 0.0240.023 0.023 0.023 0.023 0.023 0.023 0.023 107 0.025 0.024 0.025 0.0250.025 0.026 0.026 0.026 Group 4 108 0.023 0.022 0.022 0.022 0.023 0.0220.022 0.022 109 0.025 0.024 0.025 0.025 0.025 0.025 0.025 0.025 1100.023 0.023 0.023 0.023 0.023 0.023 0.023 0.022 Group 5 111 0.024 0.0230.024 0.025 0.025 0.025 0.025 0.025 112 0.024 0.024 0.024 0.024 0.0240.023 0.024 0.023 113 0.025 0.024 0.024 0.024 0.025 0.024 0.024 0.024Group 6 114 0.023 0.022 0.022 0.022 0.023 0.023 0.022 0.023 115 0.0240.023 0.023 0.022 0.023 0.023 0.023 0.023 116 0.023 0.022 0.023 0.0230.023 0.023 0.022 0.022 Group 7 117 0.023 0.022 0.023 0.024 0.024 0.0240.024 0.023 118 0.023 0.022 0.022 0.022 0.022 0.022 0.022 0.022 1190.022 0.021 0.021 0.022 0.022 0.022 0.022 0.023 Group 8 120 0.022 0.0230.023 0.023 0.022 0.022 0.022 0.022 121 0.024 0.024 0.025 0.025 0.0250.025 0.024 0.024 122 0.026 0.026 0.026 0.027 0.026 0.026 0.026 0.026Group 9 123 0.022 0.021 0.022 0.022 0.022 0.023 0.022 0.022 124 0.0260.024 0.024 0.025 0.026 0.026 0.026 0.026 125 0.024 0.022 0.023 0.0230.024 0.024 0.024 0.023 Group 10 126 0.024 0.023 0.023 0.023 0.023 0.0240.024 0.024 127 0.023 0.023 0.024 0.024 0.023 0.024 0.024 0.024 1280.024 0.024 0.024 0.024 0.024 0.024 0.024 0.024

1. A compound having a structure of Formula A, or derivative thereof,salt thereof, or stereoisomer thereof, or having any chirality at anychiral center, or tautomer, polymorph, solvate, or combination thereof:

wherein ring A is a phenyl, indolyl, naphthyl, or benzothiazolyl; X isNH, O, CH₂, CH₂CH₂, N═N, S, SO, or SO₂; Y is a linker or bond; Z is CH,CR², or N; Z¹ is C or N to form an imidazopyridine; each Z², Z³, or Z⁴is independently CH, CR², or N; each Z⁵ or Z⁶ is C or CH; each R¹, R²,and R³ is independently a substituent, and at least one of R¹, R², or R³is a substituent other than a hydrogen; m is 0, 1, 2, 3, or 4; and n is0 or a positive integer, when X is S and ring A is a phenyl, R¹ is asubstituent other than a hydrogen; when X is S and ring A is abenzothiazolyl and linked to the Z⁵ carbon and R³ is hydrogen or alkyl,R² is not only a substituent on the Z³ carbon or only a hydrogen; when Xis S and ring A is phenyl and linked to the Z⁵ carbon and R² is only asubstituent on the Z³ carbon or hydrogen and R³ is hydrogen or alkyl, R¹is not a para-substituent when R¹ is a halogen, alkoxy, hydroxyl, oramine and R² is a halogen or alkoxy; when X is S and ring A is phenyland linked to the Z⁵ carbon and R² is only a halogen substituent on theZ³ carbon or a hydrogen, R¹ is not an ortho-substituent when R¹ is anamine or halogen and R² is a halogen or alkoxy; when X is S and ring Ais a naphthyl and linked to the Z⁵ carbon, R² is not only a substituenton the Z³ carbon or hydrogen, when X is S and ring A is phenyl andlinked to the Z⁵ carbon and R¹ is a para-substituent halogen, R³ is notan alkyl or

and when X is S and ring A is a phenyl and Z¹ is N and R² is hydrogenand R³ is hydrogen, R¹ is not a para-substituent halogen.
 2. Thecompound of claim 1, wherein ring A is a phenyl linked to the Z⁵ carbonand at least one of: Y is a bond; R¹ is a para-substituent when X is NH,O, CH₂, CH₂CH₂, N═N, SO or SO₂; R² is a substituent on the Z³ carbonwhen X is NH, O, CH₂, CH₂CH₂, N═N, SO or SO₂; R² is an alkyl ester orhalo alkyl, or is not a substituent on Z³ carbon or hydrogen; R² is nota substituent on Z³ carbon or hydrogen; m is greater than 1; n isgreater than
 1. 3. The compound of claim 1, wherein ring A is linked tothe Z⁶ carbon.
 4. The compound of claim 1, wherein R² is a halogen oralkoxy substituent on the Z³ carbon when X is NH, O, CH₂, CH₂CH₂, N═N,SO or SO₂.
 5. The compound of claim 1, wherein R¹ is a para-substituentwhen X is NH, O, CH₂, CH₂CH₂, N═N, SO or SO₂.
 6. The compound of claim1, wherein R¹ is not only a para-substituent or ortho-substituent when Xis S and R² is a substituent on the Z³ carbon or a hydrogen and R3 ishydrogen or alkyl.
 7. The compound of claim 1, wherein ring A is phenylliked to the Z⁵ carbon, the structure is characterized by at least oneof: Y is a bond; R¹ is not a para-substituent that is halogen, hydroxyl,or alkoxy or an ortho-substituent that is an amine or halogen; R² is notonly a Z³ substituent of halogen or alkoxy; R² is a Z⁴ substituent; R³is a substituent other than hydrogen or straight chain alkyl; X is NH,O, CH₂, CH₂CH₂, N═N, SO or SO₂; Z⁵ carbon and Z⁶ carbon have differentsubstituents; m is at least 2; or n is at least
 2. 8. The compound ofclaim 1, wherein the structure is characterized by at least one of: Y isa bond; ring A is a benzothiazolyl or naphthyl having at least one R¹substituent; ring A is a naphthyl linked to Y through the Cl carbon(e.g., carbon adjacent to a carbon common to both rings); R¹, R², or R³includes an aryl; at least one R¹ is a meta-substituent or anortho-substituent other than amine; at least one R² is a substituent ona carbon other than the Z³ carbon; X is NH, O, CH₂, CH₂CH₂, N═N, SO orSO₂; m is at least 2; or n is at least
 2. 9. The compound of claim 1,wherein ring A is linked to the Z⁶ carbon and Z⁵ includes R³ being asubstituent other than hydrogen or alkyl when ring A is a phenyl. 10.The compound of claim 1, the compound having a structure of Formula B orderivative thereof, salt thereof, or stereoisomer thereof, or having anychirality at any chiral center, or tautomer, polymorph, solvate, orcombination thereof:

wherein R³ is not


11. The compound of claim 1, the compound having a structure of FormulaC or derivative thereof, salt thereof, or stereoisomer thereof, orhaving any chirality at any chiral center, or tautomer, polymorph,solvate, or combination thereof:

wherein each R¹ is different when ring A is a phenyl and R¹ is a halogenpara-substituent.
 12. The compound of claim 1, the compound having astructure of Formula D or derivative thereof, salt thereof, orstereoisomer thereof, or having any chirality at any chiral center, ortautomer, polymorph, solvate, or combination thereof:

wherein the structure excludes at least one of: R^(1C) being a halogen,hydroxyl, or alkoxy when rest of R groups are hydrogen; R³ is an alkyl;R^(1C) and R^(2B) each independently being a halogen, hydroxyl, oralkoxy when rest of R groups are hydrogen; R^(1A) and R^(2B) eachindependently being a halogen, when rest of R groups are hydrogen;R^(1A) being an amine and R^(2B) being a halogen, when rest of R groupsare hydrogen; R^(2B) being a halogen, hydroxyl, or alkoxy when rest of Rgroups are hydrogen; or X is S.
 13. The compound of claim 1, thecompound having a structure of Formula D or derivative thereof, saltthereof, or stereoisomer thereof, or having any chirality at any chiralcenter, or tautomer, polymorph, solvate, or combination thereof:

wherein the structure includes at least one of: R^(1C) being halogen andR^(2C) being halogen; R^(1A), R^(1C), and R^(1E) each being anon-hydrogen substituent; R^(1B), R^(1C), and R^(1D) each being anon-hydrogen substituent; R^(1A) being halogen or hydroxyl; R^(1A) beinga fluorocarbon; R^(1A) being an alkyl; R^(1A) being a non-hydrogensubstituent when R³ is an alkyl; R^(1A) being a non-hydrogen substituentwhen R^(2B) is a hydroxy or alkoxy; R^(2B) being an alkylester; R^(2B)and R^(2c) each being a non-hydrogen substituent; R^(2A) and R^(2c) eachbeing a non-hydrogen substituent; R^(2B) and R^(2D) being a non-hydrogensubstituent; R^(1A), R^(1b), R^(1C), R^(1D), R^(1E), R^(2A), R^(2B),R^(1C), R^(2D), or R³ being a haloalkyl; R³ being an alkynol; each ofR^(1A) through R^(1E) being a non-hydrogen substituent; or X is NH, O,CH₂, CH₂CH₂, N═N, SO or SO₂.
 14. The compound of claim 1, wherein thecompound is selected from the group of:3-((4-bromophenyl)thio)-6-fluoro-1H-indole (172A);2-((4-bromophenyl)thio)-3-methyl-1H-indole (172B); methyl3-((4-bromophenyl)thio)-1H-indole-5-carboxylate (172G);5-bromo-3-((4-bromophenyl)sulfinyl)-1H-indole (172I);5-bromo-3-((4-bromophenyl)sulfonyl)-1H-indole (172J);6-bromo-3-((4-bromophenyl)thio)-1H-indole (174A);5,6-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AB);5,7-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AC);5-bromo-3-((perchlorophenyl)thio)-1H-indole (174AD);4,6-dibromo-3-((4-bromophenyl)thio)-1H-indole (174AE);5-bromo-3-((4-bromophenyl)thio)-6-chloro-1H-indole (174AF);5-bromo-3-((2,4,6-trichlorophenyl)thio)-1H-indole (174AG);5-bromo-3-((3,4,5-tribromophenyl)thio)-1H-indole (174AH);2-((5-bromo-1H-indol-3-yl)thio)phenol (174AI);5-bromo-3-((2-chlorophenyl)thio)-1H-indole (174AJ);3-((2-aminophenyl)thio)-2-methyl-1H-indol-5-ol (174AK);3-((1H-indol-3-yl)thio)-5-bromo-1H-indole (174AL);3-((4-bromophenyl)thio)imidazo[1,2-a]pyridine (174AN);3-((2-hydroxyphenyl)thio)-2-methyl-1H-indol-5-ol (174AO);3-((2-hydroxyphenyl)thio)-1H-indol-5-ol (174AP);2-((5-methoxy-1H-indol-3-yl)thio)phenol (174AQ);3-((2-bromophenyl)thio)-1H-indol-5-ol (174AR);3-((2-bromophenyl)thio)-5-methoxy-1H-indole (174AS);(2-((5-bromo-1H-indol-3-yl)thio)phenyl)methanol (174AT);5-bromo-3-((2-fluorophenyl)thio)-1H-indole (174AU);5-bromo-3-((2-(trifluoromethyl)phenyl)thio)-1H-indole (174AV);3-((2-bromophenyl)thio)-5-(trifluoromethyl)-1H-indole (174AX);5-bromo-3-(o-tolylthio)-1H-indole (174AY);5-bromo-3-((2-bromophenyl)thio)-2-methyl-1H-indole (174AZ);4-bromo-3-((4-bromophenyl)thio)-1H-indole (174D);3-((4-bromophenyl)thio)-5-fluoro-1H-indole (174E);5-bromo-3-(naphthalen-1-ylthio)-1H-indole (174G);7-bromo-3-((4-bromophenyl)thio)-1H-indole (174H);5-bromo-3-((3-bromophenyl)thio)-1H-indole (174N);5-bromo-3-((4-bromobenzyl)thio)-1H-indole (174O);3-([1,1′-biphenyl]-4-ylthio)-5-bromo-1H-indole (174R);5-bromo-3-((2,3-dichlorophenyl)thio)-1H-indole (174T);5-bromo-3-((2,4-dichlorophenyl)thio)-1H-indole (174V);5-bromo-3-((3,4-dichlorophenyl)thio)-1H-indole (174W);5-bromo-2-((5-bromo-1H-indol-3-yl)thio)aniline (174X);3-((5-bromo-1H-indol-3-yl)thio)aniline (174Y);2-((5-(trifluoromethyl)-1H-indol-3-yl)thio)phenol (177A);4-((5-(trifluoromethyl)-1H-indol-3-yl)thio)phenol (177B);2-((5-(trifluoromethyl)-1H-indol-3-yl)thio)aniline (177C);3-((2-fluorophenyl)thio)-5-(trifluoromethyl)-1H-indole (177D);3-((2-bromophenyl)thio)-5-fluoro-1H-indole (177E);5-(trifluoromethyl)-3-((2-(trifluoromethyl)phenyl)thio)-1H-indole(177F); 3-((2-ethylphenyl)thio)-5-(trifluoromethyl)-1H-indole (177G);(5-bromo-3-((2-bromophenyl)thio)-1H-indol-2-yl)methanol (177H);(3-((2-ethylphenyl)thio)-5-(trifluoromethyl)-1H-indol-2-yl)methanol(177I);N-((3-((4-hydroxyphenyl)thio)-1H-indol-5-yl)methyl)-4-(triethoxysilyl)butanamide(156SI); and/or3-((2-aminophenyl)thio)-5-bromo-N-(3-(triethoxysilyl)propyl)-1H-indole-2-carboxamide(174SI).
 15. The compound of claim 1, wherein the compound is not acompound of the following group: 4-((1H-indol-3-yl)thio)phenol (156I);3-((4-bromophenyl)thio)-1H-indole (156K);3-((4-methoxyphenyl)thio)-1H-indole (1560);2,3-bis((4-bromophenyl)thio)-1H-indole (156P);3-((4-bromophenyl)thio)-2-methyl-1H-indole (172C);5-bromo-3-((4-bromophenyl)thio)-1H-indole (172D);3-((4-bromophenyl)thio)-5-methoxy-1H-indole (172E);5-bromo-3-(phenylthio)-1H-indole (174AA);3-((4-bromophenyl)thio)-5-chloro-1H-indole (174C);5-bromo-3-((2-bromophenyl)thio)-1H-indole (174I);5-bromo-3-((4-chlorophenyl)thio)-1H-indole (174J);3-(benzylthio)-5-bromo-1H-indole (174K);2-((5-bromo-1H-indol-3-yl)thio)benzo[d]thiazole (174L);2-((5-bromo-1H-indol-3-yl)thio)aniline (174M);5-bromo-3-((4-fluorophenyl)thio)-1H-indole (174P);5-bromo-3-((4-methoxyphenyl)thio)-1H-indole (174Q);5-bromo-3-(naphthalen-2-ylthio)-1H-indole (174S);3-((4-bromophenyl)thio)-1H-indole (174U); and/or4-((5-bromo-1H-indol-3-yl)thio)aniline (174Z).
 16. The compound of claim1, wherein the compound is not a compound of the following group:3-(phenylthio)-1H-indole (156L); 3-(pyridin-2-ylthio)-1H-indole (156M);2-((1H-indol-3-yl)thio)benzoic acid (156N);3-((4-bromophenyl)thio)-1H-pyrrolo[2,3-b]pyridine (172F); ethyl3-((4-bromophenyl)thio)-1H-indole-2-carboxylate (172H); and/or3-((4-bromophenyl)thio)-1-methyl-1H-indole (174B).
 17. The compound ofclaim 1, wherein at least one of R¹, R², R³ and/or R⁴ includes apolymer.
 18. The compound of claim 1, wherein at least one of R¹, R², R³and/or R⁴ includes a polyether.
 19. The compound of claim 18, whereineach R¹, R², R³ and/or R⁴ independently includes —R⁵-R⁶-R⁷, wherein: R⁵is O, NH, or a saturated or unsaturated hydrocarbon spacer of C₀-C₁₀; R⁶is a functional linker; R⁷ is a PEG or conjugation moiety.
 20. Thecompound of claim 1, wherein at least one of R² or R³ includes aconjugation moiety.
 21. The compound of claim 1, wherein at least one ofR² or R³ includes an alkyl silane or biotin.
 22. The compound of claim1, wherein at least one of R¹, R², R³ and/or R⁴ includes at least onehaloalkyl or diazirine.
 23. The compound of claim 1, wherein theantimicrobial has a structure of Formula 6 or Formula 7 or derivative,salt thereof, or stereoisomer thereof, or having any chirality at anychiral center, or tautomer, polymorph, solvate, or combination thereof,as presented herein;


24. A compound having a structure of Formula 1, or derivative thereof,salt thereof, or stereoisomer thereof, or having any chirality at anychiral center, or tautomer, polymorph, solvate, or combination thereof:

wherein ring A is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, orpolycycle combination thereof; X is NH, O, CH₂, CH₂CH₂, N═N, S, SO, orSO₂; Y is a linker or bond; Z is CH, CR², or N; Z¹ is C or N to form animidazopyridine; each Z², Z³, or Z⁴ is independently CH, CR², or N; eachZ⁵ or Z⁶ is C or CH; each R¹, R², and R³ is independently a substituent;m is 0, 1, 2, 3, or 4; and n is 0 or a positive integer, wherein atleast one R¹, R², R³ and/or R⁴ independently includes —R⁵-R⁶-R⁷,wherein: R⁵ is O, NH, or a saturated or unsaturated hydrocarbon spacerof C₀-C₁₀; R⁶ is a functional linker; R⁷ is a PEG or conjugation moiety.25. The compound of claim 1, wherein at least one conjugation moietyincludes an alkyl silane or biotin.
 26. A composition comprising: thecompound of claim 1; and a liquid carrier having the compound.
 27. Anarticle of manufacture comprising: the compound of claim 1; and a solidmaterial having the compound on a surface or body of the solid material.28. A composition comprising: the compound of claim 24; and a liquidcarrier having the compound.
 29. An article of manufacture comprising:the compound of claim 24; and a solid material having the compound on asurface or body of the solid material.